Cephem derivatives

ABSTRACT

What are disclosed are cephem compounds of the formula ##STR1## in which R 1  denotes hydrogen, an optionally substituted alkyl, acyl, arylsulfonyl or alkylsulfonyl group or an amino-protective group which is known from peptide chemistry, R 2  denotes hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aralkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl or heterocyclic group, R 3  denotes hydrogen, an ester group or a cation, R 4  denotes hydrogen, a lower alkoxy group or a group which can be converted to this, X denotes a SO group in the R or S configuration or a SO 2  group and A denotes hydrogen, an optionally substituted alkoxy or alkenyloxy group, halogen or a group --CH 2  Y, in which Y represents hydrogen, halogen or the radical of a nucleophilic compound, and in which the R 2  O group is in the syn-position, which compounds are valuable chemotherapeutic agents having a very powerful antimicrobial action against Gram-positive and Gram-negative bacteria and an unexpectedly good action against penicillinase-forming Staphilococci.

This is a continuation, of application Ser. No. 896,156, filed Apr. 13,1978, now abandoned.

The invention relates to cephem derivatives of the general formula I##STR2## in which R₁ denotes hydrogen, an optionally substituted alkyl,acyl, arylsulfonyl or alkylsulfonyl group or an aminoprotective groupwhich is known from peptide chemistry, R₂ denotes hydrogen or anoptionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aralkyl,acyl, aryl, arylsulfonyl, alkylsulfonyl or heterocyclic group, R₃denotes hydrogen, an ester group or a cation, R₄ denotes hydrogen, alower alkoxy group or a group which can be converted to this, X denotesa SO group in the R or S configuration or a SO₂ group and A denoteshydrogen, an optionally substituted alkoxy or alkenyloxy group, halogenor a group --CH₂ Y, in which Y represents hydrogen, halogen or theradical of a nucleophilic compound, and in which the R₂ O group is inthe syn-position.

The invention furthermore relates to a process for the manufacture ofcephem derivatives of the general formula I, which comprises

(a) reacting lactams of the general formula II ##STR3## wherein A, X, R³and R⁴ have the meanings indicated above, but R³ cannot representhydrogen, with reactive derivatives of a carboxylic acid of the generalformula III ##STR4## in which the radicals R¹ and R² have the meaningsindicated above, but R¹ cannot be hydrogen, or

(b) oxidising cephem compounds of the general formula IV ##STR5## inwhich the radicals R₁, R₂, R₃, R₄ and A have the meanings indicatedabove, on the sulfur of the cephem ring and, if desired, in thecompounds manufactured according to (a) or (b)

(α) converting a resulting salt into the free carboxylic acid andoptionally further esterifying this, or converting a resulting saltdirectly into an ester,

(β) saponifying a resulting ester and optionally converting theresulting product into a salt,

(γ) splitting off a radical R₁, if this denotes a protective group, and

(δ) if R₄ represents a group which can be converted into a lower alkoxygroup, carrying out this conversion, it being possible for one or moreof the reactions given under (α) to (δ) to be used.

The present invention relates to compounds of the general formula I inwhich the substituents can have, for example, the following meaning.

R₁ can represent hydrogen, optionally substituted alkyl with 1-6 carbonatoms, preferably tert.-butyl, tert.-amyl, benzyl, p-methoxybenzyl,benzhydryl, trityl and phenylethyl, benzyl, benzhydryl and trityl alsobeing amino-protective groups which are known from peptide chemistry,aliphatic acyl with 1-6, preferably 1-4, C atoms, such as, for example,formyl, acetyl or butyryl, it also being possible for such an acyl groupto be further monosubstituted or polysubstituted, for example byhalogen, such as, for example, fluorine, chlorine or bromine, which canalso lead, for example, to the chloroacetyl or trichloroacetyl radicals,which are known from peptide chemistry as amino-protective groups, byaryl, in particular phenyl, which can also carry still furthersubstituents, such as, for example, a heterocyclic radical defined underR₅ ; alkyl with 1-4 C atoms, preferably methyl; alkenyl with 1-4 Catoms, preferably allyl; alkoxy with 1-4 C atoms, preferably methoxy;alkylthio with 1-4 C atoms, preferably methylthio; halogen, preferablychlorine or bromine; sulfamoyl, carbamoyl, carboxyl or trifluoromethyl;alkoxycarbonyl with 1-4 alkyl C atoms, such as, for example,methoxycarbonyl; cyano or nitro; amino; alkylamino with 1-4 C atoms,such as, for example, methylamino or ethylamino; dialkylamino with 1-4 Catoms, such as, for example, dimethyl- or diethyl-amino, or amidino, bya nucleophilic radical, defined under Y, preferably --SR₅, by aryloxy,in particular phenoxy, by arylmercapto, in particular phenylmercapto orby arylamino, in particular phenylamino, it also being possible forthese aryloxy, arylmercapto and arylamino radicals, for example, tocarry the substituents indicated above for aryl (as a substituent of thealiphatic acyl R₁), by an optionally substituted hetero-aromatic5-membered or 6-membered ring with 1 to 4 hetero-atoms, in particularnitrogen, sulfur or oxygen, such as is described in detail under --SR₅,by hydroxyl, by alkoxy with 1-4 C atoms, in particular methoxy orethoxy, by alkylthio with 1-4 C atoms, in particular methylthio orethylthio, by alkylamino with 1-4 C atoms, in particular methylaino orethylamino, or by dialkylamino with 1-4 C atoms, in particular dimethyl-or diethyl-amino, which can be closed to form a 5-membered to 7-memberedring which can be optionally interrupted by hetero-atoms, such as, forexample, oxygen or nitrogen, such as, for example, morpholine,piperazine or N-alkyl-piperazine in which alkyl has 1-4 C atoms,preferably N-methylpiperazine, aromatic acyl, preferably benzoyl, italso being possible for the aromatic group to be substituted, such as isindicated above for the aryl substituents of the aliphatic acyl radicalR₁, hetero-aromatic acyl, the hetero-aromatic 5-membered or 6-memberedring with 1 to 4 hetero-atoms, which can also be further substituted, asdescribed above for aryl, being one such as is described in detail under--SR₅, optionally substituted alkylsulfonyl with 1-4 C atoms, inparticular methylsulfonyl or ethylsulfonyl, arylsulfonyl, preferablyphenylsulfonly, which can be substituted in the manner indicated abovefor aryl, in particular by nitro, amino or alkyl with 1-4 C atoms, suchas, for example, methyl, or an amino-protective group which is knownfrom peptide chemistry (compare, for example, Houben-Weyl, volume XV/1,page 46 (1974)), in particular alkoxycarbonyl with 1-4 alkyl C atoms,which is preferably substituted by halogen or cyano, such as, forexample, methoxycarbonyl, tert.-butoxycarbonyl, trichloroethoxycarbonylor cyano-tert.-butoxycarbonyl, or arylalkoxycarbonyl with 1-4 alkyl Catoms, in particular phenylalkoxycarbonyl, it also being possible forthe aryl radical to be further substituted, for example by nitro orlower alkoxy, preferably benzyloxycarbonyl, p-nitro- orp-methoxy-benzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl or2-biphenylyl-4-isopropoxycarbonyl, or trialkylsilyl, in which alkyl canconsist of 1-4 C atoms, such as, for example, trimethylsilyl ortert.-butyldimethylsilyl.

R₂ can denote, for example, hydrogen, alkyl with 1-4 C atoms, such as,for example, methyl, ethyl, propyl or butyl, preferably methyl, orcycloalkyl with 3-8, preferably 3-6, C atoms, such as, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, it also beingpossible for alkyl and cycloalkyl to be further monosubstituted orpolysubstituted, for example by alkyl with 1-4 C atoms, preferablymethyl, by cycloalkyl with 3-8, in particular 3-6, C atoms, such as, forexample, cyclopentyl or cyclohexyl, by alkoxycarbonyl with 1-4 alkyl Catoms, preferably methoxycarbonyl or ethoxycarbonyl, by carboxyl; cyano;carbamoyl, which can be mono-substituted or disubstituted by optionallysubstituted, for example hydroxy-substituted, alkyl with 1-4 C atoms, italso being possible for 2 substituents to be closed to form a 5-memberedor 6-membered ring which is optionally interrupted by O or N, such as,for example, morpholino, piperazino, N-methylpiperazino or pyrrolidino,by alkylcarbonyl with 1-4 alkyl C atoms, in particular acetyl, by sulfoor sulfamoyl, by alkoxysulfonyl with 1-C atoms, in particular methoxy-or ethoxy-sulfonyl, by a phosphono group, by hydroxyl, by halogen,preferably chlorine or bromine, by alkoxy with 1-4 C atoms, inparticular methoxy or ethoxy, by alkylthio with 1-4 C atoms, inparticular methylthio or ethylthio, by acyloxy, in particular aliphaticacyloxy with 1-4 C atoms, such as, for example, acetoxy or benzoyloxy,by carboxyalkoxy with 1-4 alkyl C atoms, in particular carboxymethoxy,or by aryl, preferably phenyl, which can also carry substituents, suchas are indicated for the aryl radical substituting the aliphatic acyl(R₁), alkenyl with 2-6, preferably 3-5, C atoms, such as, for example,allyl or crotonyl, which can also be further substituted, for example byalkyl with 1-4 C atoms, preferably methyl, by halogen, in particularchlorine or bromine, by carboxyl or carbamoyl, which can be substituted,as indicated above under alkyl (R₂), or by alkoxycarbonyl with 1-4 alkylC atoms, in particular methoxycarbonyl or ethoxycarbonyl, alkinyl with3-5 C atoms, preferably propargyl, which can also be furthersubstituted, for example by aryl, preferably phenyl, aliphatic,saturated or unsaturated acyl with 1-7, preferably 1-4, C atoms, suchas, for example, formyl, acetyl, propionyl, butyryl, hexanoyl, acryloyl,crotonoyl or propioloyl, which can also be further substituted, forexample by halogen, such as, for example, chlorine, bromine or fluorine,which leads, for example, to a chloroacetyl, dichloroacetyl orbromoacetyl radical, by amino, by alkylamino with 1-4 C atoms,preferably methyl- or ethyl-amino, or by dialkylamino with 1-4 C atoms,in particular dimethyl- or diethyl-amino, which can also be closed toform a ring which is optionally interrupted by hetero-atoms, such asoxygen, nitrogen or sulfur, such as, for example, morpholine, piperazineor perhydrothiazine, aromatic acyl, such as, for example, benzoyl ornaphthoyl, which can also be substituted, for example by alkyl with 1-4C atoms, in particular methyl, by halogen, preferably chlorine orbromine, by alkoxy with 1-4 C atoms, in particular methoxy, bydialkylamino with 1-4 C atoms, in particular dimethyl- or diethylamino,which can also be closed to form a ring which is optionally interruptedby hetero-atoms, such as, for example, oxygen or nitrogen and which hasalready been described above, or by trifluoromethyl, heterocyclic acyl,which is derived from heterocyclic 5-membered or 6-membered rings with 1to 4 hetero-atoms, such as, for example, sulfur, oxygen and nitrogen,such as, for example, thenoyl, furoyl, nicotinoyl, isonicotinoyl orpicolinoyl, and which can also be further substituted, for example bysubstituents such as are indicated above for aromatic acyl (R₂),optionally substituted arylsulfonyl, in particular phenylsulfonyl,p-tolysulfonyl and p-amino-phenylsulfonyl, optionally substitutedalkylsulfonyl with 1-7, preferably 1-4, C atoms, in particular methyl-or ethyl-sulfonyl, aryl, preferably phenyl, or, for example, 1- or2-naphthyl, which can also be further substituted, for example bysubstituents such as are indicated above for aromatic acyl (R₂), or aheterocyclic group, which is derived from a heterocyclic 5-membered or6-membered ring with 1-4 hetero-atoms, such as, for example, sulfur,oxygen and nitrogen, such as, for example, thienyl, furyl, pyridyl orpicolinyl, and can also be further substituted, for example bysubstituents such as are indicated above for aromatic acyl (R₂).

R₃ can represent, for example, hydrogen, an ester group or a cation.

If R₃ denotes an ester group, possible examples of this arestraight-chain or branched alkyl with 1 to 12, preferably 1 to 6, Catoms, such as, for example, methyl, ethyl, i-propyl, tert.-butyl, hexylas well as, for example, octyl or dodecyl, straight-chain or branchedalkenyl with 2 to 12, preferably 3 to 5, C atoms, such as, for example,allyl, crotyl, pentenyl as well as dodecenyl, or straight-chain orbranched alkinyl with 3-12, preferably 3-5, C atoms, such as, forexample, propinyl, butinyl, pentinyl as well as dodecinyl, it also beingpossible for these alkyl, alkenyl or alkinyl groups to bemonosubstituted or polysubstituted by identical or differentsubstituents, for example by halogen, in particular chlorine or bromine,whereby, for example, a trichloromethyl radical results, by hydroxyl, byalkoxy with 1 to 4 C atoms, in particular methoxy or ethoxy, once ortwice, preferably twice, by carbocyclic or heterocyclic aryl, such as,in particular, phenyl, or radicals which are derived fromhetero-aromatic 5-membered or 6-membered rings with 1 to 4 hetero-atoms,such as, for example, sulfur, oxygen and nitrogen, such as, for example,thienyl, furyl or pyridyl, which can also carry still furthersubstituents, for example those which have been given above in detailfor the aryl substituent of the aliphatic acyl group (R₁), bycarbocyclic or heterocyclic aryloxy, such as, in particular, phenoxy, orradicals which are derived from hetero-aromatic 5-membered or 6-memberedrings with 1 to 4 hetero-atoms, such as, for example, sulfur, oxygen andnitrogen, such as, for example, pyridinoxy, which can also carry furthersubstituents, such as have been indicated above, for example, for thearyl substituent of the alkyl radical R₃, by carboxyl or cyano, bycarbamoyl, which can also be substituted, for example by one or twoalkyl groups with 1-4 C atoms, preferably methyl; or lower aralkyl,preferably benzyl, by alkoxycarbonyl with 1-4 alkyl C atoms, such as,for example, methoxycarbonyl, by alkylcarbonyloxy with 1-6, preferably1-4, alkyl C atoms, such as acetoxy, pivaloyloxy or also hexanoyloxy, bycycloalkylcarbonyloxy with 3-7 cycloalkyl C atoms, such as, for example,cyclohexylcarbonyloxy, by aroyloxy, such as, for example, benzoyloxy, bycarbocyclic or heterocyclic arylalkylcarbonyl with 1-4 alkyl C atoms,such as, for example, phenylacetyl or thienylacetyl, by carbocyclic orheterocyclic aryloxyalkylcarbonyl with 1-4 alkyl C atoms, such as forexample phenoxyacetyl or thienyloxy acetyl, by alkylcarbonyl with 1-6,preferably 1-4, alkyl C atoms, such as, for example, acetyl, propionylor butyryl, which can also be monosubstituted or polysubstituted, forexample by oxyimino; alkoxyimino, as defined in more detail under R₂, inparticular methoxyimino; or alkoxycarbonyl with 1-4 alkyl C atoms, inparticular methoxy- or ethoxycarbonyl; by carbocyclic or heterocyclicarylcarbonyl, such as, for example, benzoyl or thenoyl, which can alsocarry further substituents, such as, for example, alkyl with 1-4 Catoms, such as, preferably, methyl or ethyl; alkoxy with 1-4 C atoms,preferably methoxy or ethoxy; halogen, preferably chlorine or bromine;sulfamoyl; trifluoromethyl; alkylamino with 1-4 C atoms, such as methyl-or ethyl-amino; or dialkylamino with 1-4 C atoms, such as dimethyl- ordiethyl-amino, which can also be closed to form a 5-membered to7-membered ring which is optionally interrupted by hetero-atoms, suchas, for example, oxygen, nitrogen or sulfur, such as, for example,morpholine or piperazine, or by optionally substituted aryl, preferablyphenyl, trialkylsily with 1-4 C atoms in the alkyl group, such as, forexample, trimethylsilyl, or indanyl or phthalidyl.

If R₃ denotes a cation, it represents an inorganic metal ion or anorganic ammonium ion. Examples which may be mentioned are, inparticular, pharmacologically acceptable alkali metal ions or alkalineearth metal ions, preferably the sodium, potassium, calcium or magnesiumion, the ammonium ion and, from the organic ammonium ions, inparticular, an optionally substituted, alkylated ammonium ion, such as,for example, the triethylammonium or diethanolammonium ion, as well asthe morpholineammonium, benzylammonium, procaineammonium,L-arginineammonium and L-lysineammonium ion.

R₄ can represent, for example, hydrogen, lower alkoxy with 1-4 C atoms,preferably methoxy, or a group which can be converted into such analkoxy group, such as, for example, halogen, preferably bromine, orsaturated or unsaturated alkylthio with 1-4 C atoms, such as, forexample, methylthio, ethylthio, i-propylthio or allylthio.

A can denote, for example, hydrogen, alkoxy with 1-4 C atoms, such asmethoxy, ethoxy or butoxy, in particular methoxy, it also being possiblefor the alkyl chain, with the exception of that having 2 C atoms, to besubstituted, for example by hydroxyl or by halogen, preferably chlorineor bromine, alkoxycarbonyl with 1-4 alkyl C atoms, in particularmethoxy- or ethoxy-carbonyl, alkenyloxy with 3-6 C atoms, such as, forexample, allyloxy, which can be substituted in the same manner as thealkoxy group (A) above, halogen, preferably chlorine or bromine, or--CH₂ Y, wherein Y, in addition to hydrogen or halogen, such as, forexample, fluorine, chlorine or bromine, can also represent the radicalof a nucleophilic compound.

Examples which may be mentioned of such radicals of a nucleophiliccompound, preferably of a S-, N- or O-nucleophilic compound, areacyloxy, hydroxyl, alkoxy, amino, alkyl- or dialkyl-amino, mercapto,optionally substituted pyridinium, quinolinium or isoquinolinium,optionally substituted carbamoyloxy or carbamoylthio, azido or a group--SR₅, wherein R₅ denotes an optionally substituted acyl, alkyl or arylradical or an optionally substituted 5-membered or 6-memberedheterocyclic ring which is optionally fused to an aromatic 5-membered or6-membered ring, or the radical ##STR6## in which Z represents sulfur oroxygen and R₆ and R₇, which can be identical or different, representalkyl, alkenyl, alkoxy, alkenyloxy, optionally substituted phenyl or acarbocyclic ring with 3-8 C atoms.

Some of the groups which are possible, according to the invention, asthe nucleophilic radical Y are illustrated in more detail in thefollowing text.

If Y represents acyloxy, possible acyl radicals are, for example,aliphatic acyl radicals with 1-4 C atoms, such as, for example, acetoxyor propionyloxy. Acetoxy is particularly preferred.

If Y represents alkoxy, possible radicals here are straight-chain orbranched alkoxy radicals with, for example, 1-8 C atoms, preferably with1-4 C atoms, such as, for example, methyl, ethyl, n-propyl, i-propyl,n-butyl or i-butyl.

If Y represents a pyridine, quinoline or isoquinoline radical, it isbonded via nitrogen and can be substituted, for example by lower alkyl,such as, for example, methyl or ethyl, lower alkoxy, such as, forexample, methoxy or ethoxy, or carbamoyl. However, it is preferablyunsubstituted.

If Y represents a carbamoyloxy or carbamoylthio group, this group can bemonosubstituted or polysubstituted on the nitrogen, for example by loweralkyl with 1-4 C atoms, such as, for example, methyl or ethyl, it alsobeing possible for the two substituents to be linked with one another toform a ring, for example to form a 5-membered or 6-membered ring, whichcan also be interrupted by a hetero-atom, such as, for example, oxygen,sulfur or nitrogen. The unsubstituted carbamoyl group is preferred.

Y can furthermore represent azido, as well as monosubstituted ordisbustituted amino. Possible substituents are, in particular, alkylwith 1-4 C atoms, such as, for example, methyl or ethyl, it also beingpossible, in the case of a dialkylamino group, for the substituents tobe closed to form a 5-membered or 6-membered ring which is optionallyinterrupted by hetero-atoms, such as, for example, morpholine orpiperazine. The amino group ca, for example, also be substituted byalkoxy with 1-4 C atoms, such as, for example, methoxy or ethoxy, or byaryl, preferably phenyl, which can also carry further substituents, suchas, for example, alkyl with 1-4 C atoms, preferably methyl, sulfamoyl,trifluoromethyl or halogen, such as, for example, chlorine or bromine.

If Y denotes amino, in order to avoid the formation of a ring R₃ mustrepresent an ester group. This can also then be appropriate if Y denotesa hydroxyl, mercapto or monosubstituted amino group.

If Y represents a group --SR₅ and R₅ represents an acyl radical,possible acyl radicals are optionally substituted aliphatic, aromatic orheterocyclic acyl radicals, for example aliphatic acyl with 1-4 C atoms,such as, for example, acetyl or propionyl, aromatic acyl, such as, forexample, benzoyl or toluoyl, and heterocyclic acyl which is derived from5-membered or 6-membered rings with 1-4 hetero-atoms, such as, forexample, nitrogen, sulfur or oxygen, such as, for example, nicotinoyl,isonicotinoyl, picolinoyl, furoyl, thenoyl, thiazoloyl, oxazoloyl,triazoloyl or thiadiazoloyl. The acetyl and propionyl radicals arepreferred. R₅ can also denote optionally substituted aryl, preferablyphenyl, the substituents corresponding to those which can be in the arylsubstituting the aliphatic acyl radical (R₁).

If R₅ denotes an alkyl radical, a possible radical here isstragiht-chain or branched alkyl with, for example, 1-8 C atoms,preferably 1-4 C atoms, such as, for example, methyl, ethyl, n-propyl,i-propyl, n-butyl or i-butyl, in particular methyl and ethyl, which canalso be optionally substituted, for example by amino, hydroxyl, carboxylor carbalkoxy with 1-4 alkyl C atoms, in particular methoxycarbonyl, orby phenyl which is optionally substituted by alkyl or alkoxy with 1-4 Catoms, in particular methyl or methoxy, nitro or halogen, in particularchlorine or bromine.

If R₅ represents a heterocyclic radical, possible radicals areoptionally substituted five-membered or six-membered rings which have 1to 4 hetero-atoms, such as, for example, oxygen, sulfur and/or nitrogen,in particular nitrogen, optionally together with sulfur or oxygen asring atoms.

If the radical R₅ denotes a heterocyclic radical, it can also be bondedto a fused aromatic 5-membered or 6-membered ring system, for example apyridine or triazole ring, preferably to a benzene ring, but theheterocyclic ring which is not fused to a ring system is preferred. Theheterocyclic ring system which forms the radical R₅ can also becompletely or partially hydrogenated, but preferably non-hydrogenated.

The following fundamental ring systems may be mentioned as examples ofthe radical R₅ : thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl and purinyl, as well asbenzo-fused derivatives, for example benzoxazolyl, benzthiazolyl,benzimidazolyl and indolyl.

5-membered ring systems with a sulfur or oxygen atom and 1 to 3 nitrogenatoms, such as thiazolyl, in particular thiazol-2-yl and thiazol-2-ylN-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, andoxadiazolyl, such as 1,3,4-oxadiazol-5-yl, are preferred. Furthermore,5-membered ring systems with 2 to 4 nitrogen atoms, such as imidazolyl,preferably imidazol-2-yl, triazolyl, preferably 1,3,4-triazol-5-yl and1,2,3- and 1,2,4-triazol-5-yl, and tetrazolyl, preferably 1H-tetrazol-5-yl and 2 H-tetrazolyl, are preferred. Benzofusedderivatives, in particular benzoxazol-2-yl, benzthiazol-2-yl andbenzimidazol-2-yl, are also preferred.

Furthermore, preferred possible ring systems are 6-membered ring systemswith 1 to 3, preferably 1 to 2, nitrogen atoms, such as, for example,pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl, pyrimidyl,preferably pyrimid-2-yl and pyrimid-4-yl, triazinyl, preferably1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl, pyridazinyl, in particularpyridazin-3-yl, and pyrazinyl. The pyridyl, pyrimid-2-yl, pyrimid-4-yland pyridazinyl radicals, in particular the pyridine N-oxides andpyridazine N-oxides, are preferred.

If the radical R₅ denotes a heterocyclic radical, it can bemonosubstituted or polysubstituted, examples of possible substituentsbeing the following: straight-chain or branched alkyl groups with, forexample, 1 to 15 carbon atoms, such as, for example, methyl, ethyl,n-propyl, i-propyl, n-butyl, tert.-butyl, n-hexyl, undecyl andpentadecyl, preferably those with 1-4 carbon atoms, such as, forexample, methyl and ethyl, as well as lower alkyl groups with 1 to 4carbon atoms, such as, for example, methyl, which are substituted, forexample by aryl, such as, for example, phenyl or thienyl, by aryloxy,for example phenoxy, by low-molecular alkoxy, such as, for example,methoxy and ethoxy, by lower alkoxycarbonyl, such as, for example,methoxy- or ethoxy-carbonyl, by halogen, such as, for example, chlorineor bromine, by hydroxyl, by aliphatic acylamido, preferably with 1 to 4C atoms, such as, for example, acetamido, by aromatic acylamido, suchas, for example, benzamido, by amino, by alkylamino with 1 to 4 C atoms,such as, for example, methyl- or ethyl-amino, by dialkylamino with 1-4 Catoms, such as, for example, dimethyl- or diethylamino, it also beingpossible for the alkyl radicals of the dialkylamino group to be closedto form a 5-membered to 7-membered ring which is optionally interruptedby hetero-atoms, such as, for example, oxygen or nitrogen, such as, forexample, morpholino or piperazino, by trifluoromethyl, by cyano, bycarbamoyl, by carboxyl, by carboxyalkoxy with 1-4 alkyl C atoms, suchas, for example, carboxymethoxy, by cyanoalkoxy with 1 to 4 alkyl Catoms, such as, for example, cyanomethoxy, by carbamoylalkoxy with 1-4alkyl C atoms, such as, for example, carbamoylmethoxy, byalkoxycarbonyloxy with 1-4 alkyl C atoms, such as, for example,methoxycarbonyloxy, by sulfo, by alkylsulfo, preferably with 1-4 Catoms, such as, for example, methylsulfonyl, by sulfamoyl, byphosphonyl, by alkylcarbamoyl with 1-4 alkyl C atoms, such as, forexample, methylcarbamoyl, by dialkylcarbamoyl with 1-4 alkyl C atoms,such as, for example, dimethylcarbamoyl, by alkyl- or dialkylsulfamoylwith 1-4 C atoms, such as, for example, methyl- or dimethyl-sulfamoyl,by carboxyalkylcarboxamido, preferably with 1-4 alkyl C atoms, such as,for example, succinamic acid, by cyanoalkylcarboxamido, preferably with1-4 alkyl C atoms, such as, for example, malonic acid mononitrile-amide,or by alkoxycarbonylalkylcarboxamido, preferably with 1-4 C atoms ineach alkyl group, it also being possible for the carboxamido nitrogen tobe further substituted, such as, for example, methyl-succinamate andmethyl N-methyl-succinamate.

If R₅ denotes a heterocyclic radical, it can furthermore be substitutedby cycloalkyl with 3 to 8 C atoms, such as, for example, cyclopentyl andcyclohexyl, or by alkoxy with 1-4 C atoms, such as, for example, methoxyand ethoxy, alkenyl with 2-4 C atoms, such as, for example, allyl,alkenyloxy with 3-5 C atoms, such as, for example, allyloxy, alkyl- andalkenyl-thio with 1-4 C atoms, such as, for example, methylthio andallylthio, alkoxycarbonyl with 1-4 alkyl C atoms, such as, for example,methoxycarbonyl, alkylcarbonyl with 1-4 alkyl C atoms, such as, forexample, acetyl, arylcarbonyl, such as, for example, benzoyl,carboxyalkoxycarbonyl with 1-4 C atoms, such as, for example,carboxymethoxycarbonyl, cyanoalkoxycarbonyl with 1-4 alkyl C atoms, suchas, for example, cyanomethoxycarbonyl, carbamoylalkoxycarbonyl with 1 to4 alkyl C atoms, such as, for example, carbamoylmethoxycarbonyl,alkoxycarbonylamino with 1-4 alkoxy C atoms, such as, for example,ethoxycarbonylamino, carboxyalkylthio with 1-4 alkyl C atoms, such as,for example, carboxymethylthio, amino, arylamino, such as, for example,phenylamino, heteroarylamino, such as, for example, pyrid-2-yl-amino andpyrid-4-yl-amino, monoalkyl- and dialkyl-amino with 1-4 C atoms, suchas, for example, methylamino, dimethylamino, ethylamino anddiethylamino, it also being possible for the two alkyl substituents tobe closed to form a 5-membered to 7-membered ring which is optionallyinterrupted by hetero-atoms, such as, for example, oxygen or nitrogen,such as, for example, morpholino, piperidino, pyrrolidino andpiperazino, carboxyalkylamino with 1-4 alkyl C atoms, such as, forexample, carboxymethylamino, cyanoalkylamino with 1-4 alkyl C atoms,such as, for example, cyanomethylamino, alkoxycarbonylalkylamino with1-4 alkoxy and alkyl C atoms, such as, for example,methoxycarbonylmethylamino, sulfoalkylamino with 1-4 C atoms, such as,for example, sulfomethylamino, sulfamoylalkylamino with 1 to 4 C atoms,such as, for example, sulfamoylmethylamino, alkylsulfamoylalkylaminowith 1-4 alkyl C atoms in each case, such as, for example,methylsulfamoylmethylamino, dialkylsulfamoylalkylamino with 1-4 alkyl Catoms in each case, such as, for example, dimethylsulfamoylmethylamino,alkoxysulfonylalkylamino with 1-4 alkoxy and alkyl C atoms, such as, forexample, methoxysulfonylmethylamino, oxido, hydroxyl, hydroxyalkyl with1-4 alkyl C atoms, such as, for example, hydroxymethyl and hydroxyethyl,carboxyalkylcarbonyloxy with 1-4 alkyl C atoms, such as, for example,carboxymethylcarbonyloxy, cyanoalkylcarbonyloxy with 1 to 4 alkyl Catoms, such as, for example, cyanomethylcarbonyloxy,alkoxycarbonylalkylcarbonyloxy with 1-4 alkyl C atoms in each case, suchas, for example, methoxycarbonylmethylcarbonyloxy, carboxyalkoxy with1-4 alkyl C atoms, such as, for example, carboxymethoxy, cyanoalkoxywith 1-4 alkyl C atoms, such as, for example, cyanomethoxy,alkoxycarbonylalkoxy with 1-4 alkoxy C atoms, such as, for example,methoxycarbonylmethoxy, carbamoylalkoxy with 1-4 alkyl C atoms, such as,for example, carbamoylmethoxy, carbamoylalkylcarbonyloxy with 1-4 alkylC atoms, such as, for example, carbamoylmethylcarbonyloxy, sulfoalkoxywith 1-4 C atoms, such as, for example, sulfomethoxy, sulfamoylalkoxywith 1-4 C atoms, such as, for example, sulfamoylmethoxy, nitro, cyano,halogen, preferably chlorine, trifluoromethyl, mercapto, carboxyl,carbamoyl, carboxyalkylaminocarbonyl with 1-4 alkyl C atoms, such as,for example, carboxymethylaminocarbonyl, carbamoylalkylaminocarbonylwith 1-4 alkyl C atoms, such as, for example,carbamoylmethylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl with 1-4alkoxy and alkyl C atoms, such as, for example,methoxycarbonylmethylaminocarbonyl, aryl radicals, such as, for example,phenyl, substituted phenyl, such as, for example, alkoxyphenyl with 1-4alkoxy C atoms, such as, for example, methoxyphenyl and ethoxyphenyl,halogenophenyl, such as, for example, chlorophenyl, hydroxyphenyl,aminophenyl, alkylamino- or dialkylamino-phenyl with 1-4 alkyl C atoms,such as, for example, methylamino- or dimethylamino-phenyl, alkylphenyl,in particular alkylphenyl with 1-4 alkyl C atoms, such as, for example,tert.-butylphenyl, tolyl or cetylphenyl, hydroxyalkylphenyl with 1-4alkyl C atoms, such as, for example, hydroxyethylphenyl,halogenoalkylphenyl with 1-4 alkyl C atoms, such as, for example,trifluoromethylphenyl or chloromethylphenyl, alkoxyalkylphenyl with 1-4alkoxy and alkyl C atoms, such as, for example, methoxymethylphenyl,alkenylphenyl with 2 to 6, preferably 3-5, alkenyl C atoms, such as, forexample, allylphenyl, alkenyloxyphenyl with 2-6, preferably 3-5,alkenyloxy C atoms, such as, for example, allyloxyphenyl, cyanophenyl,carbamoylphenyl, carboxyphenyl, alkoxycarbonylphenyl with 1-4 alkyl Catoms, such as, for example, methoxycarbonylphenyl,alkylcarbonyloxyphenyl with 1-4 alkyl C atoms, such as, for example,acetoxyphenyl, sulfophenyl, alkoxysulfophenyl with 1-4 alkoxy C atoms,such as, for example, methoxysulfophenyl, sulfamoylphenyl, nitrophenyl,biphenyl or optionally correspondingly substituted naphthyl radicals orheterocyclic radicals which are derived from heterocyclic 5-membered or6-membered rings with 1 to 4 hetero-atoms, in particular nitrogen,sulfur or oxygen, such as, for example, pyridyl, furyl, quinolyl,isoquinolyl, thienyl, thiazolyl, N-pyrrolyl, pyrrolyl, imidazolyl,pyrazolyl, isoxazolyl, tetrazolyl and triazolyl.

If R₅ denotes a heterocyclic radical, possible substituents are also:cyanoalkylaminocarbonyl with 1-4 C atoms, such as, for example,cyanomethylaminocarbonyl, carboxyalkylcarboxamido with 1-4 C atoms, suchas, for example, succinamic acid, alkoxyalkylcarboxamido with 1-4 Catoms, such as, for example, methylsuccinamate, cyanoalkylcarboxamidowith 1-4 C atoms, such as, for example, malonic acid nitrile-monoamide,alkylcarbamoyl with 1-4 C atoms, such as, for example,methylaminocarbonyl, dialkylcarbamoyl with 1-4 C atoms, such as, forexample, dimethylaminocarbonyl, it also being possible for the two alkylradicals to be closed to form a carbocyclic ring with 5-7 C atoms, whichcan be interrupted by nitrogen, sulfur or oxygen, such as, for example,morpholinocarbonyl, alkoxycarbonylalkoxyalkyl with 1-4 C atoms, such as,for example, methoxycarbonylmethoxyalkyl, alkylcarbamoylalkoxyalkyl with1-4 C atoms, such as, for example, methylcarbamoylmethoxymethyl,alkoxyalkylaminocarbonylalkyl, such as, for example,methoxymethylaminocarbonylmethyl, an amino group or an amino group whichis monosubstituted by lower alkyl, it being possible for the amino groupto be acylated by lower aliphatic or aromatic carboxylic acids, such as,for example, acetamido or benzamido, as well as an aryl orhetero-aromatic radical which is substituted by trifluoromethyl oralkylcarboxyl with 1-4 C atoms. The number of C atoms, 1-4, indicated inthis paragraph in each case relates to an alkyl group contained in theradicals.

Of the 5-membered rings with 2-4 hetero-atoms, such as nitrogen, sulfurand oxygen, preferably at least one heteroatom being nitrogen, and6-membered rings with 1-3 heteroatoms, in particular nitrogen atoms,which are preferred, according to the invention, for R₅, the followingradicals of the general formulae II-VII may be mentioned as examples ofparticularly preferred radicals. In the definitions of the substituents,in each case "lower" denotes a carbon atom number of 1-4, or, in thecase of an unsaturated radical, a C atom number of 2-4.

(a) A thiazolyl radical of the general formula V ##STR7## in which R₈and R₉ can be identical or different and represent hydrogen,straight-chain or branched lower alkyl, which can be optionallysubstituted by halogen, lower alkoxy, hydroxyl, amino, lower alkylamino,lower dialkylamino, trifluoromethyl or phenyl, straight-chain orbranched lower alkenyl, a carbocyclic ring with 3-8 carbon atoms, amino,lower alkylamino, lower dialkylamino, lower aliphatic acylamido, lowercarboxyalkyl, lower alkoxycarbonylalkyl, lower carbamoylalkyl, carboxyl,carbamoyl, cyano, cyanoalkyl, lower alkoxycarbonyl, lowercarboxyalkylaminocarbonyl, lower alkoxycarbonylalkylaminocarbonyl,cyanoalkylaminocarbonyl, lower carboxyalkylcarboxamido, loweralkoxycarbonylalkylcarboxamido, lower cyanoalkylcarboxamido, lowercarboxyalkylthio, an optionally substituted hetero-aryl radical or aphenyl radical which is optionally substituted by one or two halogenatoms, lower alkyl, lower alkoxy, hydroxyl, lower alkylamino, lowerdialkylamino, lower alkylthio, cyano or trifluoromethyl, it beingpossible for R₈ and R₉ together to form an optionally substitutedcarbocyclic ring with 5-7 carbon atoms, and n represents 0 or 1.

Examples which may be mentioned are, in particular: 1,3-thiazol-2-yl,4-methyl-1,3-thiazol-2-yl, 4-tert.-butyl-1,3-thiazol-2-yl,4-n-propyl-1,3-thiazol-2-yl, 4-ethyl-1,3-thiazol-2-yl,5-amino-1,3-thiazol-2-yl, 5-acetamido-1,3-thiazol-2-yl,5-methylamino-1,3-thiazol-2-yl, benzothiazol-2-yl,5-chloro-benzothiazol-2-yl, 4-methyl-3-oxy-1,3-thiazol-2-yl,3-oxy-4-phenyl-1,3-thiazol-2-yl,4-(4-chlorophenyl)-3-oxy-1,3-thiazol-2-yl, 3-oxy-1,3-thiazol-2-yl,4-(4-bromophenyl)-3-oxy-1,3-thiazol-2-yl,3-oxy-4-(p-tolyl)-1,3-thiazol-2-yl,4-(p-methoxyphenyl)-3-oxy-1,3-thiazol-2-yl,4-methyl-3-oxy-5-phenyl-1,3-thiazol-2-yl,5-methyl-3-oxy-4-phenyl-1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl,4-trifluoromethyl-1,3-thiazol-2-yl, 4-phenyl-1,3-thiazol-2-yl,4,5-dimethyl-1,3-thiazol-2-yl, 4-(3-pyridyl)-1,3-thiazol-2-yl,4-carboxymethyl-1,3-thiazol-2-yl, 3-carboxy-4-methyl-1,3 -thiazol-2-yl,4-carboxy-1,3-thiazol-2-yl, 4-ethoxycarbonyl-5-amino-1,3-thiazol-2-yl,5-amino-4-carboxy-1,3-thiazol-2-yl,5-carboxymethylaminocarbonyl-1,3-thiazol-2-yl,5-carboxymethylcarboxamido-1,3-thiazol-2-yl,5-carboxymethyl-4-phenyl-1,3-thiazol-2-yl,4-(5-nitro-thien-2-yl)-1,3-thiazol-2-yl,4-(4-carboxythien-2-yl)-1,3-thiazol-2-yl,4-(1-methyl-pyrrol-2-yl)-1,3-thiazol-2-yl,4-(5-carbamoyl-fur-2-yl)-1,3-thiazol-2-yl and5-carboxy-4-methyl-1,3-thiazol-2-yl.

(b) A pyridyl radical of the general formula VI ##STR8## in which R¹⁰ toR¹³ can be identical or different and denote hydrogen, halogen, lower,straight-chain or branched alkyl or alkenyl, trifluoromethyl, loweralkylcarbonyl, amino, lower alkylamino, lower dialkylamino, carboxyl,carbamoyl, cyano, lower alkylaminocarbonyl, lower dialkylaminocarbonyl,lower alkoxycarbonyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, loweralkylthio or nitro and n represents 0 or 1.

Examples which may be mentioned are, in particular: 1-oxy-pyrid-2-yl,3-methyl-1-oxy-pyrid-2-yl, 4-methyl-1-oxy-pyrid-2-yl, 1-oxy-pyrid-4-yl,5-methyl-1-oxy-pyrid-2-yl, 6-methyl-1-oxy-pyrid-2-yl,3-ethoxy-1-oxy-pyrid-2-yl, 5-bromo-1-oxy-pyrid-2-yl, pyrid-2-yl,pyrid-3-yl, pyridin-4-yl, 3-hydroxy-pyrid-2-yl, 3-nitro-pyrid-2-yl,5-nitro-pyrid-2-yl, 2-amino-6-methyl-pyrid-3-yl,4-chloro-1-oxy-pyridin-2-yl, 2-carboxy-pyrid-4-yl, 3-carboxy-pyrid-5-yland 4-carboxy-pyrid-5-yl.

(c) Oxadiazolyl, thiadiazolyl and triazolyl radicals of the generalformulae VII, VII a and VII b ##STR9## in which Q represents oxygen,sulfur or >N-R¹⁵ and G represents oxygen or sulfur, and wherein R¹⁴denotes hydrogen, lower, straight-chain or branched alkyl, lowerstraight-chain or branched alkenyl, a carbocyclic ring with 5-7 carbonatoms, hydroxyl, lower hydroxyalkyl, lower alkoxy, lower alkylthio,lower alkoxyalkyl, an amino group, which can be optionally substitutedby one or two lower alkyl radicals which together can also form acarbocyclic ring with 5-7 carbon atoms, lower aliphatic or aromaticacylamido, a lower aminoalkyl group, which can be optionally substitutedby one or two lower, branched or straight-chain alkyl radicals, whichtogether can also form a carbocyclic ring with 5-7 carbon atoms, oracylated by a lower aliphatic or aromatic carboxylic acid,trifluoromethyl, lower alkoxycarbonylalkylamido, lowercarboxyalkylamido, lower cyanoalkylamido, loweralkoxycarboxyalkoxyalkyl, lower carboxyalkyl, lower alkoxycarbonylalkyl,lower cyanoalkyl, carboxyl, carbamoyl, cyano, lower carbamoylalkyl,lower alkoxycarbonyl, lower alkylcarbamoyl, lower dialkylcarbamoyl,lower sulfoalkyl, lower sulfamoylalkyl, lower alkylsulfamoylalkyl, lowerdialkylsulfamoylalkyl, lower alkylcarbamoylalkyl, lowerdialkylcarbamoylalkyl, lower alkoxycarbonylalkoxyalkyl, lowercarboxyalkoxyalkyl, lower carbamoylalkoxyalkyl, loweralkylcarbamoylalkoxyalkyl, lower alkoxyalkylaminocarbonylalkyl, lowercarboxyalkylthio and an aryl or heterocyclic radical, preferably aphenyl, naphthyl, thienyl, furyl, thiazolyl, pyrrolyl, imidazolyl,pyrazolyl, isoxazolyl, quinolyl, isoquinolyl or pyridyl radical, whichis optionally substituted by one or two halogen atoms, hydroxyl, loweralkoxy, lower, straight-chain or branched alkyl, lower, straight-chainor branched alkenyl, trifluoromethyl, cyano, amino, carboxyl, loweralkoxycarbonyl, sulfo, carbamoyl, sufamoyl, lower alkylcarboxy, loweralkylcarbonyl, lower alkylamino, nitro or lower dialkylamino, or anarylamino or heteroarylamino group or lower arylalkyl, and in which R¹⁵can be hydrogen, lower straight-chain or branched alkyl, lowerstraight-chain or branched alkenyl, lower carboxyalkyl, loweralkoxycarbonylalkyl, lower cyanoalkyl, lower sulfoalkyl, lowersulfamoylalkyl, lower alkylsulfamoylalkyl, lower dialkylsulfamoylalkyl,lower alkylcarbamoylalkyl, lower dialkylcarbamoylalkyl, loweralkoxycarbonylalkoxyalkyl, lower carboxyalkoxyalkyl, lowercarbamoylalkoxyalkyl, lower alkylcarbamoylakoxyalkyl, hydroxyl, lowerhydroxyalkyl, an amino group which can be optionally acylated with alower aliphatic carboxylic acid or alkylated with one or two lower alkylradicals, lower arylalkyl, lower alkoxyalkyl, a carbocyclic ring with 5to 7 carbon atoms, a pyrrolyl radical, which can be optionallysubstituted by one or two lower alkyl groups, or an aryl or heterocyclicradical, preferably a phenyl or pyridine radical, which can beoptionally substituted by carboxyl, cyano, trifluoromethyl, carbamoyl,amino, lower alkylamino, lower dialkylamino, lower alkyl, sulfo,sulfamoyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, loweralkylcarbonyl or lower alkoxy.

Examples which may be mentioned are, in particular: for ##STR10##1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-phenyl-1,3,4-oxadiazol-5-yl, 2-(4-fluorophenyl)-1,3,4-oxadiazol-5-yl,2-(2-bromophenyl)-1,3,4-oxadiazol-5-yl,2-(2-methoxyphenyl)-1,3,4-oxadiazol-5-yl,2-cyclohexyl-1,3,4-oxadiazol-5-yl, 2-(2-pyridyl)-1,3,4-oxadiazol-5-yl,2-(3-pyridyl)-1,3,4-oxadiazol-5-yl, 2-(4-pyridyl)-1,3,4-oxadiazol-5-yl,2-(2-furyl)-1,3,4-oxadiazol-5-yl, 2-(3-furyl)-1,3,4-oxadiazol-5-yl,2-(2-thienyl)-1,3,4-oxadiazol-5-yl, 2-propyl-1,3,4-oxadiazol-5-yl,2-butyl-1,3,4-oxadiazol-5-yl, 2-(2-hydroxyphenyl)-1,3,4-oxadiazol-5-yl,2-ethyl-1,3,4-oxadiazol-5-yl, 2-(4-nitrophenyl)-1,3,4-oxadiazol-5-yl,2-(3-thienyl)-1,3,4-oxadiazol-5-yl,2-(4-chlorophenyl)-thienyl-1,3,4-oxadiazol-5-yl,2-(2-thiazolyl)-1,3,4-oxadiazol-5-yl,2-(3-nitrophenyl)-1,3,4-oxadiazol-5-yl,2-(2-tolyl)-1,3,4-oxadiazol-5-yl, 2-(3-tolyl)-1,3,4-oxadiazol-5-yl,2-(4-hydroxyphenyl)-1,3,4-oxadiazol-5-yl, 2-benzyl-1,3,4-oxadiazol-5-yl,2-(1-naphthyl)-1,3,4-oxadiazol-5-yl,2-(2-pyrrolyl)-1,3,4-oxadiazol-5-yl,2-(4-imidazolyl)-1,3,4-oxadiazol-5-yl,2-(5-pyrazolyl)-1,3,4-oxadiazol-5-yl,2-(3,5-dimethyl-4-isoxazolyl)-1,3,4-oxadiazol-5-yl,2-(ethoxycarbonylmethoxymethyl)-1,3,4-oxadiazol-5-yl,2-(carboxymethoxymethyl)-1,3,4-oxadiazol-5-yl,2-carbamoyl-1,3,4-oxadiazol-5-yl,2-(N-methylcarbamoyl)-1,3,4-oxadiazol-5-yl,2-(N-ethylcarbamoyl)-1,3,4-oxadiazol-5-yl,2-(N,N-dimethylcarbamoyl)-1,3,4-oxadiazol-5-yl and2-(N,N-dimethylaminomethyl)-1,3,4-oxadiazol-5-yl, for ##STR11##1,3,4-thiadiazol-5-yl, 2-butyl-1,3,4-thiadiazol-5-yl,2-propyl-1,3,4-thiadiazol-5-yl, 2-phenyl-1,3,4-thiadiazol-5-yl,2-amino-1,3,4-thiadiazol-5-yl, 2-ethyl-1,3,4-thiadiazol-5-yl,2-acetamido-1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl,2-(N-methylacetamido)-1,3,4-thiadiazol-5-yl,2-isobutylamino-1,3,4-thiadiazol-5-yl,2-piperidino-1,3,4-thiadiazol-5-yl, 2-pyrrolidino-1,3,4-thiadiazol-5-yl,2-aminomethyl-1,3,4-thiadiazol-5-yl,2-acetamidomethyl-1,3,4-thiadiazol-5-yl,2-benzamido-1,3,4-thiadiazol-5-yl,2-(β-piperidinoethyl)-1,3,4-thiadiazol-5-yl,2-(2-pyridylamino)-1,3,4-thiadiazol-5-yl,2-(3-pyridylamino)-1,3,4-thiadiazol-5-yl,2-(1,3-thiazol-2-yl-amino)-1,3,4-thiadiazol-5-yl,2-(1,3,4-triazolyl-2-amino)-1,3,4-thiadiazol-5-yl,2-(tetrazolyl-5-amino)-1,3,4-thiadiazol-5-yl,2-dimethylaminomethyl-1,3,4-thiadiazol-5-yl,2-methylaminomethyl-1,3,4-thiadiazol-5-yl,2-ethyl-1,3,4-thiadiazol-5-yl, 2-trifluoromethyl-1,3,4-thiadiazol-5-yl,2-methylthio-1,3,4-thiadiazol-5-yl, 2-(2-pyridyl)-1,3,4-thiadiazol-5-yl,2-(3-pyridyl)-1,3,4-thiadiazol-5-yl,2-(4-pyridyl)-1,3,4-thiadiazol-5-yl,2-(2-thienyl)-1,3,4-thiadiazol-5-yl, 2-(2-furyl)-1,3,4-thiadiazol-5-yl,2-(3-furyl)-1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl,2-isopropyl-1,3,4-thiadiazol-5-yl,2-(4-methoxyphenyl)-1,3,4-thiadiazol-5-yl,2-(4-chlorophenyl)-1,3,4-thiadiazol-5-yl,2-(1-naphthyl)-1,3,4-thiadiazol-5-yl,2-(2-quinolyl)-1,3,4-thiadiazol-5-yl,2-(1-isoquinolyl)-1,3,4-thiadiazol-5-yl, 2-(β-methoxycarbonylpropionylamido)-1,3,4-thiadiazol-5-yl,2-(β-carboxypropionylamido)-1,3,4-thiadiazol-5-yl,2-carboxymethoxymethyl-1,3,4-thiadiazol-5-yl,2-ethoxycarbonylmethyl-1,3,4-thiadiazol-5-yl,2-carboxymethyl-1,3,4-thiadiazol-5-yl,2-(α-carboxyacetamido)-1,3,4-thiadiazol-5-yl,2-(α-cyanoacetamido)-1,3,4-thiadiazol-5-yl,2-methoxycarbamoyl)-acetamido-1H-1,3,4-thiadiazol-5-yl,2-(N,N-dimethylcarbamoylmethyl)-1H-1,3,4-thiadiazol-5-yl,2-(N,N-diethylcarbamoylmethyl)-1H-1,3,4-thiadiazol-5-yl,2-(N,N-dipropylcarbamoylmethyl)-1H-1,3,4-thiadiazol-5-yl,2-(N,N-dibutylcarbamoylmethyl)-1H-1,3,4-thiadiazol-5-yl,2-(2-acetamidoethyl)-1,3,4-thiadiazol-5-yl,2-(2-aminoethyl)-1,3,4-thiadiazol-5-yl,2-hydroxymethyl-1,3,4-thiadiazol-5-yl,2-(2-hydroxyethyl)-1,3,4-thiadiazol-5-yl,2-(isobutyryloxymethyl)-1,3,4-thiadiazol-5-yl,2-(ethoxycarbonylmethoxymethyl)-1,3,4-thiadiazol-5-yl,2-(carbamoylmethoxymethyl)-1,3,4-thiadiazol-5-yl,2-(N-methylcarbamoyl)-1,3,4-thiadiazol-5-yl,2-isobutyl-1,3,4-thiadiazol-5-yl,2-methoxypropylaminocarbonylmethyl-1,3,4-thiadiazol-5-yl,2-carboxyethyl-1,3,4-thiadiazol-5-yl,2-sulfoethyl-1,3,4-thiadiazol-5-yl, 2-carboxy-1,3,4-thiadiazol-5-yl,2-phenylamino-1,3,4-thiadiazol-5-yl,2-o-carboxybenzoylamino-1,3,4-thiadiazol-5-yl,2-(1-carboxyethylthio)-1,3,4-thiadiazol-5-yl and2-(1-carboxy-1-methylethyl)-1,3,4-thiadiazol-5-yl, for ##STR12##1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl and3-phenyl-1,2,4-oxadiazol-5-yl, for ##STR13## 1,2,4-thiadiazol-5-yl,3-phenyl-1,2,4-thiadiazol-5-yl, 3-methylmercapto-1,2,4-thiadiazol-5-yl,3-methyl-1,2,4-thiadiazol-5-yl and 3-ethyl-1,2,4-thiadiazol-5-yl, for##STR14## 2-methyl-1H-1,3,4-triazol-5-yl, 2-ethyl-1H-1,3,4-triazol-5-yl,2-amino-1H-1,3,4-triazol-5-yl, 1H-1,3,4-triazol-5-yl,2-trifluoromethyl-1H-1,3,4-triazol-5-yl,2-(β-piperidinoethyl)-1H-1,3,4-triazol-5-yl,2-(β-diethylaminoethyl)-1H-1,3,4-triazol-5-yl,2-hydroxy-1H-1,3,4-triazol-5-yl, 2-(4-pyridyl)-1H-1,3,4-triazol-5-yl,2-tert.-butyl-1H-1,3,4-triazol-5-yl,2-(3-pyridyl)-1H-1,3,4-triazol-5-yl,2-(2-pyridyl)-1H-1,3,4-triazol-5-yl, 2-acetamido-1H-1,3,4-triazol-5-yl,2-propionylamido-1H-1,3,4-triazol-5-yl,2-benzamido-1H-1,3,4-triazol-5-yl, 2-(2-thienyl)-1H-1,3,4-triazol-5-yl,2-(2-furyl)-1H-1,3,4-triazol-5-yl, 2-(3-furyl)-1H-1,3,4-triazol-5-yl,2-methoxymethyl-1H-1,3,4-triazol-5-yl,2-(4-sulfamoylphenyl)-1H-1,3,4-triazol-5-yl,2-phenyl-1H-1,3,4-triazol-5-yl,2-(4-methoxyphenyl)-1H-1,3,4-triazol-5-yl,2-(4-chlorophenyl)-1H-1,3,4-triazol-5-yl,2-(2-methylpyrid-4-yl)-1H-1,3,4-triazol-5-yl,2-phenoxymethyl)-1H-1,3,4-triazol-5-yl,2-ethoxymethyl-1H-1,3,4-triazol-5-yl,2-(2-ethoxyethyl)-1H-1,3,4-triazol-5-yl,2-aminoethyl-1H-1,3,4-triazol-5-yl,2-acetamidomethyl-1H-1,3,4-triazol-5-yl,2-ethoxycarbonylmethyl-1H-1,3,4-triazol-5-yl,2-(β-carbomethoxypropionylamido)-1H-1,3,4-triazol- 5-yl,2-carboxymethyl-1H-1,3,4-triazol-5-yl,2-carboxymethoxymethyl-1H-1,3,4-triazol-5-yl,2-ethoxycarbonylmethoxymethyl-1H-1,3,4-triazol-5-yl,2-ethoxycarbonyl-1H-1,3,4-triazol-5-yl,2-carbamoyl-1H-1,3,4-triazol-5-yl,2-carbamoylmethoxymethyl-1H-1,3,4-triazol-5-yl and2-(N-ethylcarbamoylmethoxymethyl)-1H-1,3,4-triazol-5-yl, for ##STR15##in which R¹⁵ ≠ hydrogen 2-amino-1-methyl-1,3,4-triazol-5-yl,1-methyl-1,3,4-triazol-5-yl,1-methyl-2-trifluoromethyl-1,3,4-triazol-5-yl,1,2-dimethyl-1,3,4-triazol-5-yl, 2-hydroxy-1-methyl-1,3,4-triazol-5-yl,1-methyl-2-(3-pyridyl)-1,3,4-triazol-5-yl,1-methyl-2-(4-pyridyl)-1,3,4-triazol-5-yl,2-(2-furyl)-1-methyl-1,3,4-triazol-5-yl,1-methyl-2-(2-thienyl)-1,3,4-triazol-5-yl,1-methyl-2-(2-pyridyl)-1,3,4-triazol-5-yl,2-(3-furyl)-1-methyl-1,3,4-triazol-5-yl,1-methyl-2-phenyl-1,3,4-triazol-5-yl, 1-ethyl-1,3,4-triazol-5-yl,1-ethyl-2-(3-pyridyl)-1,3,4-triazol-5-yl,1-ethyl-2-(4-pyridyl)-1,3,4-triazol-5-yl,1-ethyl-2-(2-pyridyl)-1,3,4-triazol-5-yl,2-(3-furyl)-1-methyl-1,3,4-triazol-5-yl,1-ethyl-2-trifluoromethyl)-1,3,4-triazol-5-yl,1-ethyl-2-(2-furyl)-1,3,4-triazol-5-yl,1-ethyl-2-(2-thienyl)-1,3,4-triazol-5-yl,1,2-diethyl-1,3,4-triazol-5-yl,1-propyl-2-(3-pyridyl)-1,3,4-triazol-5-yl,2-(2-furyl)-1-propyl-1,3,4-triazol-5-yl, 1-propyl-1,3,4-triazol-5-yl,1-isopropyl-1,3,4-triazol-5-yl, 1-allyl-1,3,4-triazol-5-yl,1-butyl-1-(2-furyl)-1,3,4-triazol-5-yl, 1-cyclohexyl-1,3,4-triazol-5-yl,1-benzyl-1,3,4-triazol-5-yl, 1-hydroxy-1,3,4-triazol-5-yl,1-methoxymethyl-1,3,4-triazol-5-yl, 1-phenyl-1,3,4-triazol-5-yl,2-methyl-1-phenyl-1,3,4-triazol-5-yl,1-(4-chlorophenyl)-1,3,4-triazol-5-yl,2-hydroxy-1-phenyl-1,3,4-triazol-5-yl,2-amino-1-phenyl-1,3,4-triazol-5-yl,1-phenyl-2-propyl-1,3,4-triazol-5-yl,2-(1-piperidinomethyl)-1-phenyl-1,3,4-triazol-5-yl,2-(β-diethylaminoethyl)-1-phenyl-1,3,4-triazol-5-yl,1-(4-ethoxyphenyl)-2-(β-piperidinoethyl)-1,3,4-triazol-5-yl,1-(4-chlorophenyl)-2-dimethylaminomethyl-1,3,4-triazol-5-yl,1-phenyl-2-(4-pyridyl)-1,3,4-triazol-5-yl,1-(3-pyridyl)-1,3,4-triazol-5-yl,2-hydroxy-1-(2-pyridyl)-1,3,4-triazol-5-yl,1-(4-pyridyl)-1,3,4-triazol-5-yl, 1-(2-pyridyl)-1,3,4-triazol-5-yl,1-(4-ethoxyphenyl)-2-hydroxy-1,3,4-triazol-5-yl,1-(4-chlorophenyl)-2-hydroxy-1,3,4-triazol-5-yl,1-amino-2-trifluoromethyl-1,3,4-triazol-5-yl,1-amino-2-(2-hydroxyphenyl)-1,3,4-triazol-5-yl,1-amino-2-phenyl-1,3,4-triazol-5-yl,1-amino-2-(4-fluorophenyl)-1,3,4-triazol-5-yl,1-amino-2-(2-bromophenyl)-1,3,4-triazol-5-yl,1-amino-2-(2-methoxyphenyl)-1,3,4-triazol-5-yl,1-amino-2-(4-pyridyl)-1,3,4-triazol-5-yl,1-amino-2-(2-thienyl)-1,3,4-triazol-5-yl,1-amino-2-cyclohexyl-1,3,4-triazol-5-yl,1-amino-2-methyl-1,3,4-triazol-5-yl, 2-ethyl-1-amino-1,3,4-triazol-5-yl,2-phenyl-1-phenylamino-1,3,4-triazol-5-yl,2-ethyl-1-ethylamino-1,3,4-triazol-5-yl,1-amino-2-methylthio-1,3,4-triazol-5-yl,1-amino-2-mercapto-1,3,4-triazol-5-yl,1-amino-2-benzyl-1,3,4-triazol-5-yl,1-acetamido-2-ethyl-1,3,4-triazol-5-yl,2-ethyl-1-(2,5-dimethyl-pyrrol-1-yl)-1,3,4-triazol-5-yl,2-ethyl-1-(pyrrol-1-yl)-1,3,4-triazol-5-yl,1-methyl-2-(4-sulfamoylphenyl)-1,3,4-triazol-5-yl,1-allyl-2-(4-sulfamoylphenyl)-1,3,4-triazol-5-yl,1-phenyl-2-(4-sulfamoylphenyl)-1,3,4-triazol-5-yl,1-amino-1,3,4-triazol-5-yl, 1-(4-ethoxyphenyl)-2-(4-pyridyl)-1,3,4-triazol-5-yl, 1-(4-ethoxyphenyl)-2-(3-pyridyl)-1,3,4-triazol-5-yl,1-(4-methoxyphenyl)-2-(4-pyridyl)-1,3,4-triazol-5-yl,1-(4-ethoxyphenyl)-2-phenyl-1,3,4-triazol-5-yl,1-(4-ethoxyphenyl)-2-(4-aminophenyl)-1,3,4-triazol-5-yl,1,2-diphenyl-1,3,4-triazol-5-yl, 1,2-di-p-tolyl-1,3,4-triazol-5-yl,1-allyl-2-phenyl-1,3,4-triazol-5-yl,1-amino-2-carboxymethyl-1,3,4-triazol-5-yl,2-carboxymethyl-1-methyl-1,3,4-triazol-5-yl,2-carboxymethoxymethyl-1-methyl-1,3,4-triazol-5-yl,1-carboxymethyl-2-trifluoromethyl-1,3,4-triazol-5-yl,1-carbamoylmethyl-2-trifluoromethyl-1,3,4-triazol-5-yl,1-sulfoethyl-2-trifluoromethyl-1,3,4-triazol-5-yl,2-ethoxycarbonylmethoxymethyl-1-methyl-1,3,4-triazol-5-yl,2-carbamoyl-1-methyl-1,3,4-triazol-5-yl,2-carbamoylmethoxymethyl-1-methyl-1,3,4-triazol-5-yl,2-ethoxycarbonyl-1-(4-methoxybenzyl)-1,3,4-triazol-5-yl and1-amino-2-carboxymethylthio-1,3,4-triazol-5-yl, and for ##STR16##1H-1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,1,4-dimethyl-1,2,3-triazol-5-yl, 1H-4-methyl-1,2,3-triazol-5-yl,1,4-diethyl-1,2,3-triazol-5-yl, 4-carboxy-1H-1,2,3-triazol-5-yl,4-(2-carboxyethyl)-1H-1,2,3-triazol-5-yl,4-(3-carboxypropyl)-1H-1,2,3-triazol-5-yl,4-(1-carboxy-1-methylethyl)-1H-1,2,3-triazol-5-yl,4-(2-carboxy-2-methylpropyl)-1H-1,2,3-triazol-5-yl,4-N-methylcarbamoyl-1H-1,2,3-triazol-5-yl,4-N-ethylcarbamoyl-1H-1,2,3-triazol-5-yl,4-N-propylcarbamoyl-1H-1,2,3-triazol-5-yl and4-N-butylcarbamoyl-1H-1,2,3-triazol-5-yl.

(d) A triazolyl radical of the general formula VIII ##STR17## in whichR¹⁶ and R¹⁷, which can be identical or different, denote lowerstraight-chain or branched alkyl, lower straight-chain or branchedalkenyl, lower alkoxyalkyl, hydroxyl, hydroxyalkyl, lower alkoxy, loweralkylcarbonyl or an optionally substituted phenyl radical, andfurthermore R¹⁶ can represent hydrogen.

Examples which may be mentioned are, in particular:1-methyl-1,2,4-triazol-5-yl, 1-butyl-1,2,4-triazol-5-yl,1-phenyl-1,2,4-triazol-5-yl, 1-methoxymethyl-1,2,4-triazol-5-yl,1,3-dimethyl-1,2,4-triazol-5-yl, 1-allyl-1,2,4-triazol-5-yl,3-hydroxy-1-methyl-1,2,4-triazol-5-yl,3-hydroxy-1-isopropyl-1,2,4-triazol-5-yl,3-hydroxy-1-phenyl-1,2,4-triazol-5-yl,3-ethyl-1-methyl-1,2,4-triazol-5-yl and3methyl-1-phenyl-1,2,4-triazol-5-yl.

(e) A pyrimidinyl and pyridazinyl radical of the general formulae IX, IXa and IX b ##STR18## in which R¹⁸ to R²⁰, which can be identical ordifferent, denote hydrogen, halogen, lower straight-chain or branchedalkyl, lower straight-chain or branched alkenyl, mercapto, loweralkylthio, hydroxyl, lower hydroxyalkyl, lower alkoxy, loweralkylcarbonyl, lower alkoxyalkyl, an amino group which can be optionallysubstituted by one or two lower alkyl radicals, lower carboxyalkyl,carboxyl, cyano, lower alkoxycarbonyl, a carbamoyl group which can beoptionally substituted by one or two lower alkyl groups, which in turncan form a carbocyclic ring with 5-7 C atoms which can be optionallyinterrupted by nitrogen or sulfur, lower alkoxycarbonylalkylamido, lowercarboxyalkylamido, lower cyanoalkyl, an optionally substituted phenylradical or lower carboxyalkylthio and the heterocyclic rings can also bepartially hydrogenated and n represents 0 or 1.

Examples which may be mentioned are, in particular: for ##STR19##4,6-diamino-pyrimidin-2-yl, 4-amino-6-hydroxy-pyrimidin-2-yl,5,6-diamino-4-hydroxy-pyrimidin-2-yl, 4,5-diamino-pyrimidin-2-yl,4-hydroxy-6-methyl-pyrimidin-2-yl, 4,6-dihydroxy-pyrimidin-2-yl,4-hydroxy-pyrimidin-2-yl, 4-hydroxy-6-propyl-pyrimidin-2-yl,pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl,4-mercapto-pyrimidin-2-yl, 4-methylthio-pyrimidin-2-yl,1,4,5,6-tetrahydropyrimidin-2-yl,4-hydroxy-6-methyl-pyrimidin-2-yl-5-acetic acid,4-hydroxy-pyrimidin-2-yl-5-carboxylic acid,4-amino-pyrimidin-2-yl-5-carboxylic acid, methyl4-amino-pyrimidin-2-yl-5-carboxylate, ethyl4-amino-pyrimidin-2-yl-5-carboxylate, 4-hydroxy-pyrimidin-2-yl-5-aceticacid, 4-hydroxy-5-piperidino-carbonyl-pyrimidin-2-yl,4-chloro-pyrimidin-2-yl-5-carboxylic acid,4-(β-carboxy-propionylamido)-6-hydroxy-pyrimidin-2-yl and5-cyanoethyl-4-hydroxy-6-methylpyrimidin-2-yl, for ##STR20##2-hydroxy-pyrimidin-4-yl, pyrimidin-4-yl,5-ethoxycarbonyl-6-methyl-2-phenyl-pyrimidin-4-yl,6-ethoxy-5-ethoxycarbonyl-2-phenyl-pyrimidin-4-yl,5-ethoxycarbonyl-6-amino-2-phenyl-pyrimidin-4-yl,5-cyano-2-hydroxy-6-methyl-pyrimidin-4-yl,5-acetyl-2,6-dimethyl-pyrimidin-4-yl,5-ethoxycarbonyl-2,6-dimethyl-pyrimidin-4-yl,2-hydroxy-6-methyl-pyrimidin-4-yl, 6-mercapto-2-methyl-pyrimidin-4-yl,6-mercaptopyrimidin-4-yl, 2-amino-6-mercapto-pyrimidin-4-yl,6-mercapto-2-methylthio-pyrimidin-4-yl,6-carboxymethylthio-pyrimidin-4-yl,6-carboxymethylthio-2-methyl-pyrimidin-4-yl and2-amino-4-carboxymethylthio-pyrimidin-4-yl, and for ##STR21##6-methoxy-2-oxy-pyridazin-3-yl, 6-butoxy-2-oxy-pyridazin-3-yl,6-ethoxy-2-oxy-pyridazin-3-yl, 6-chloro-2-oxy-pyridazin-3-yl,2-oxy-pyridazin-3-yl, 6-methyl-1-oxy-pyridazin-3-yl,6-methyl-2-oxy-pyridazin-3-yl, pyridazin-3-yl, 6-hydroxy-pyridazin-3-yl,6-chloro-1-oxy-pyridazin-3-yl,5-ethoxycarbonyl-6-hydroxy-pyridazin-3-yl,5-carboxy-6-hydroxy-pyridazin-3-yl,4-ethoxy-carbonyl-6-hydroxy-pyridazin-3-yl,4-methyl-6-hydroxy-pyridazin-3-yl, 4-ethyl-6-hydroxy-pyridazin-3-yl,5-ethoxycarbonyl-6-hydroxy-4-methyl-pyridazin-3-yl,5-ethoxycarbonyl-4-ethyl-6-hydroxy-pyridazin-3-yl,4-ethoxycarbonyl-5-ethyl-6-hydroxy-pyridazin-3-yl,4-ethoxycarbonyl-6-hydroxy-5-methylpyridazin-3-yl and6-mercaptopyridazin-3-yl.

(f) A tetrazolyl radical of the general formula X ##STR22## in which R²¹represents hydrogen, lower straight-chain or branched alkyl, lowerbranched or straight-chain alkenyl, lower alkoxyalkyl, an optionallysubstituted aryl or heteroaryl radical, a carbocyclic ring with 5-7 Catoms, lower arylalkyl, lower carboxyalkyl, lower cyanoalkyl, loweralkoxycarbonylalkyl, lower sulfoalkyl, lower sulfamoylalkyl, loweralkylsulfoalkyl, lower alkylsulfamoylalkyl, lower dialkylsulfamoylalkyl,lower carbamoylalkyl, lower alkylcarbamoylalkyl, lowerdialkylcarbamoylalkyl, lower aminoalkyl, lower hydroxyalkyl or loweralkylamidoalkyl.

Examples which may be mentioned are, in particular: tetrazol-5-yl,1-ethyl-tetrazol-5-yl, 1-allyl-tetrazol-5-yl, 1-phenyl-tetrazol-5-yl,1-butyl-tetrazol-5-yl, 1-benzyl-tetrazol-5-yl,1-(4-fluorophenyl)-tetrazol-5-yl, 1-isopropyl-tetrazol-5-yl,1-(2-pyridyl)-tetrazol-5-yl, 1-cyclohexyl-tetrazol-5-yl,1-(2,4-dichlorophenyl)-tetrazol-5-yl, 1-(2-tolyl)-tetrazol-5-yl,1-(4-nitrophenyl)-tetrazol-5-yl, 1-(4-dimethylaminophenyl)-5-yl,1-methoxymethyl-tetrazol-5-yl, 1-methyl-tetrazol-5-yl,1-propyl-tetrazol-5-yl, 1-cyclopentyl-tetrazol-5-yl,1-(4-chlorophenyl)-tetrazol-5-yl, 1-carboxymethyl-tetrazol-5-yl,1-carboxyethyl-tetrazol-5-yl, 1-cyanomethyl-tetrazol-5-yl,1-sulfomethyl-tetrazol-5-yl, 1-sulfoethyl-tetrazol-5-yl,1-sulfopropyl-tetrazol-5-yl, 1-sulfamoyl-tetrazol-5-yl,1-sulfamoylethyl-tetrazol-5-yl,1-(2-N,N-dimethyl-sulfamoylethyl)-tetrazol-5-yl,1-(3-sulfamoylpropyl)-tetrazol-5-yl,1-(2-sulfo-1-methylethyl)-tetrazol-5-yl, 1-(4-sulfobutyl)-tetrazol-5-yl,1-(2-carbamoylethyl)-tetrazol-5-yl,1-(N-methylcarbamoylmethyl)-tetrazol-5-yl, 1-(N,N-dimethylcarbamoylmethyl)-tetrazol-5-yl,1-(2-carbamoylpropyl)-tetrazol-5-yl, 1-(3-carboxypropyl)-tetrazol-5-yl,1-(2-carboxy-1-methylethyl)-tetrazol-5-yl,1-(4-dimethylaminophenyl)-tetrazol-5-yl, 1-acetamidoethyl-tetrazol-5-yl,1-(2-hydroxyethyl)-tetrazol-5-yl, 1-ethoxycarbonylmethyl-tetrazol-5-yl,1-(2-aminoethyl)-tetrazol-5-yl and 1-(3-methoxypropyl)-tetrazol-5-yl.

If in the definition of the radicals R⁸ to R²¹ substituents orreferences to particular ring systems occur which are not explained inmore detail, they correspond to the preceding statements concerning thegeneral substitution possibilities of the radical R⁵ in the meaning of"heterocyclic radical". At the same time, they are illustrated furtherby the particular accompanying tabular summary of specific radicals.

Further examples of heterocyclic R₅ radicals which may be mentioned are:1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl,1,2,3-oxadiazol-5-yl, 4,5-dimethyl-oxazol-2-yl, 4-phenyl-oxazol-2-yl,benzoxazol-2-yl, oxazolin-2-yl, imidazol-2-yl, imidazolin-2-yl,benzimidazolin-2-yl, 1-methyl-imidazolin-2-yl, 2-furyl, 2-thiophenyl,2-pyrrolyl, 2-thiazolinyl, 3-isoxazolyl, 3-pyrazolyl, thiatriazol-5-yl,purin-yl, pyrazinyl, 2-methylmercapto-6-phenyl-1,3,5-triazin-4-yl,5-methyl-6-hydroxy-1,3,4-triazin-2-yl,5-phenyl-4H-1,3,4-thiadiazin-2-yl, 5-hydroxy-4H-1,3,4-thiadiazin-2-yl,3-hydroxy-tetrazol-[4,5-b]-pyridazin-6-yl andtetrazol-[4,5-b]-pyridazin-6-yl.

If R⁵ represents the radical ##STR23## the radicals R⁶ and R⁷, which canbe identical or different, can have the following meanings:straight-chain or branched alkyl with 1-4 C atoms, such as, for example,methyl, ethyl, propyl, butyl or isobutyl, preferably methyl,straight-chain or branched alkenyl with 2-4 C atoms, such as, forexample, allyl, straight-chain or branched alkoxy with 1-4 C atoms, suchas, for example, methoxy, ethoxy, propoxy or isobutoxy, straight-chainor branched alkenyloxy with 1-4 C atoms, such as, for example, allyloxy,aryl, in particular phenyl, which can also be substituted, for exampleby alkyl or alkoxy with 1-4 C atoms, in particular methyl or methoxy, orby halogen, in particular chlorine, or a carbocyclic ring with 3-8 Catoms, such as, for example, cyclohexyl.

Examples which may be mentioned are, in particular:

(α) If Y denotes ##STR24## the radical of dimethyl-dithiophosphinicacid, butyl-methyl-dithiophosphinic acid, ethylmethyl-dithiophosphinicacid, isobutyl-methyl-dithiophosphinic acid,methyl-phenyl-dithiophosphinic acid, diphenyl-dithiophosphinic acid,O-methyl-methyl-dithiophosphonic acid, O-ethyl-methyl-dithiophosphonicacid, O-ethyl-ethyl-dithiophosphonic acid,O-ethyl-propyl-dithiophosphonic acid,O-methyl-(4-methoxyphenyl)-dithiophosphonic acid,O-methyl-isobutyl-dithiophosphonic acid,O-methyl-cyclohexyl-dithiophosphonic acid, O,O-dimethyl-dithiophosphoricacid, O,O-diethyl-dithiophosphoric acid andO,O-di-propyl-dithiophosphoric acid, and

(β) if Y denotes ##STR25## the radical of O-methyl-methyl-thiophosphonicacid, O-ethyl-methyl-thiophosphonic acid, isobutyl-methyl-thiophosphinicacid, O-ethyl-ethyl-thiophosphonic acid andO-ethyl-propyl-thiophosphonic acid.

The nomenclature of R. S. Cahn, Ch. ingold and V. Prelog, Angew. Chemie78 (1966), page 413, is used for characterising the configuration of theSO group in the cephem ring. An SO group in the R configuration has anoxygen atom in the α-position and a SO group in the S configuration hasan oxygen atom in the β-position. α and β are previous designations forasymmetric atoms and are customary, in particular, in the case ofnaturally occurring substances.

In order to obtain the compounds of the formula I with the R₂ O group inthe syn-position, which in the present text is represented throughout as##STR26## to differentiate from the anti-position ##STR27## it isappropriate to ensure that the starting material of the general formulaIII is already present as the syn-compound. If the mild reactionconditions customary for reactions with syn-compounds are then adheredto, synend products are as a rule obtained. Nevertheless it cansometimes happen that a small amount of the corresponding anticompoundis also obtained as an impurity in the end product, and, if desired,this can be separated by methods which are known in the laboratory, suchas, for example, recrystallisation.

Lactams of the general formula II which can be employed according to theinvention are described in Dutch Patent application No. 7,309,912.Possible starting materials are lactams of the formula XI ##STR28##wherein A, R₃ and R₄ have the meanings indicated above. The lactams ofthe formula XI are known from the literature or can be manufacturedaccording to information in the literature, for example according to theinformation in E. F. Flynn, Cephalosporins and Penicillins, Chemistryand Biology, Academic Press, New York and London, 1972, or GermanOffenlegungsschrift No. 2,359,402.

The lactams of the formula XI can preferably be oxidized in the form ofthe free acids or in the form of esters, but also in the form of salts.It is advantageous to protect the 7-amino group by amino-protectivegroups which can be easily split off, such as are customary, forexample, in peptide chemistry. Examples of groups which may be used andcan be split off under acid conditions are: tert.-butyl, benzhydryl,tert.-butoxycarbonyl, trityl, benzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl and trialkylsilyl, such as, for example,trimethylsilyl. Protection of the amino group in the form of a Schiff'sbase, which can be split under acid conditions, by reaction withreactive carbonyl compounds, such as, for example, benzaldehyde,salicylaldehyde, p-nitrobenzaldehyde, furfurol, 5-nitrofurfurol,acetylacetone or ethyl acetoacetate, has also proved suitable. TheSchiff's base can also be split by reaction with hydrazine and itsderivatives, preferably a Girard reagent, phenylhydrazine or2,4-dinitrophenylhydrazine.

Examples of suitable methods for oxidizing the sulfur in the cephem ringare the methods which are known from the literature which lead to theformation of SO and SO₂ bonds by the oxidation of sulfides, such as aredescribed, for example, by F. Korte in Methodicum Chimicum, volume 7(1976), Hauptgruppenelemente und deren Verbindungen (Main Group Elementsand their Compounds), pages 693-698, and the oxidizing agents mentionedin the Dutch application given above or in E. F. Flynn, Cephalosporinsand Penicillins, Chemistry and Bilogy, Academic Press, New York andLondon, 1972, preferably photosensitized oxidation using oxygen,peroxides, hydroperoxides, peracids, singlet-oxygen, hydrogen peroxideand mixtures thereof with inorganic or organic, oxidation-resistantacids, such as, for example, phosphoric acid, formic acid, acetic acidand trifluoroacetic acid. The peracids can also be produced in situ bymixing the acids with hydrogen superoxide. 3-Chloroperbenzoic acid isadvantageously employed direct.

Suitable solvents for the oxidation are all the solvents which arestable under the reaction conditions, such as, for example, dioxan,tetrahydrofuran, chloroform, methylene chloride, acetic acid, formicacid, trifluoroacetic acid, glycol dimethyl ether, benzene,chlorobenzene, tetramethylurea, dimethylformamide and dimethylacetamide.

The reaction conditions and the amount of oxidizing agent depend on thedesired end product and on the substituents present on the cephemskeleton. 2 oxidation equivalents (corresponding to one active oxygenatom) or a slight excess are sufficient for the manufacture of the R andS sulfoxides. The oxidation to the sulfone requires at least 4 oxidationequivalents, an excess of oxidizing agent also being possible in orderto accelerate the reaction.

The reaction temperatures can be between about -20° and +80° C., but theoxidation, above all in the case of the manufacture of the sulfoxides,is carried out at as low a temperature as possible, preferably -20° to+20° C.

Derivatives of the formula XI which are protected on the 7-amino groupin the form of a Schiff's base are particularly suitable for themanufacture of the lactams of the formula II with the R configuration.Acyl amino-protective groups on the 7-amino group give predominantly1-sulfoxides with the S configuration.

The separation and characterization of R and S sulfoxides is achieved onthe basis of their different solubilities and their different migrationrates in chromatographic separations. A further differentiation betweenthe R and S sulfoxides is achieved with the aid of NMR spectroscopy(compare the literature by E. H. Flynn indicated above).

The amino-protective groups are split off under the conditions for theparticular protective group, which are indicated in the literature. IfR₃ is a group which is unstable towards acid, such as, for example,tert.-butyl, and if this is to be retained for secondary reactions,suitable amino-protective groups are, in particular, those which can besplit off using hydrazine derivatives, thioureas or bases.

The carboxylic acids of the general formula III used, according to theinvention, for acylating the lactams of the general formula II can bemanufactured by various processes.

Thus, for example, compounds of the formula III in which R₁ denoteshydrogen and R₂ denotes acyl are obtained by reaction of thiourea with##STR29## and subsequent saponification of the ester group, whereby thereaction should appropriately be effected with a stoichiometric amountof thiourea at room temperature in a water-containing solvent, such as,for example, acetone, and the reaction should not be carried out forlonger than a few hours, for example a maximum of about 2-3 hours.

It is also possible to react the α-carbonyl group of a2-aminothiazole-4-glyoxylic acid alkyl or aralkyl ester, substituted onthe amino group by R₁, with a hydroxylamine compound of the generalformula H₂ N-OR₂ and then to saponify the resulting ester in a mannerwhich is in itself known.

The manufacture of the aminothiazole-glyoxylic acid esters used for thisreaction is described in German Patent application No. P 2,710,902.0.Most of the hydroxylamine derivatives required for the reaction areknown, or they can be easily manufactured according to the informationin the literature.

The reaction of the two components is carried out under the conditions,described in the literature, for the reaction of glyoxylic acidderivatives with hydroxylamine and its O-derivatives.

Compounds of the formula III in which R₁ represents an acyl group can beobtained easily and in high yields by acylating the compounds describedabove of the general formula ##STR30## in which Z' represents loweralkyl or aralkyl, with reactive carboxylic acid derivatives.

It has proved favorable to use acid halides, in particular acidchlorides and acid bromides. However, it is particularly advantageous toemploy symmetric or unsymmetric anhydrides. The acylation is carried outin the presence of bases, such as, for example, triethylamine,preferably at room temperature or, in particular, at temperatures whichare lowered still further, in organic solvents which do not interferewith the reaction, in particular in halogenated hydrocarbons, such as,for example, methylene chloride, chloroform or tetrachloroethylene. Theresulting esters are then converted into the free carboxylic acids.

If in the formula III R₁ in the meaning of acyl represents an aliphaticacyl radical which is also substituted by a nucleophilic radical definedunder Y, such as, for example, a nitrogen- or oxygen-nucleophile, but inparticular by the S-nucleophilic group R₅ -S-, R₅ having the meaningindicated above, the acylation described above is appropriately carriedout with activated α-halogenoalkyl acid derivatives, such as, forexample, chloroacetyl chloride, α-bromopropionyl chloride or bromoacetylbromide, which can also further carry a aryl, preferably phenyl, in theα-position, and the halogen is then reacted with a mercaptan of theformula HS-R₅ and thus replaced by --SR₅.

The replacement reaction is carried out in organic or inorganicsolvents, preferably in water, in the presence of organic or inorganicbases, such as, for example, triethylamine or sodium bicarbonate, forexample at temperatures between about 10° and 80° C., but in particularat room temperature.

If in the formula III the radical R₁ represents an arylsulfonyl oralkylsulfonyl group, these compounds of the formula III are obtained byreacting activated alkylsulfonic acid derivatives or arylsulfonic acidderivatives with compounds of the formula ##STR31## and then saponifyingthe product.

Possible activated sulfonic acid derivatives are, in particular, thesulfonic acid halides known from the literature, such as, for example,sulfonic acid chlorides, as well as the symmetric anhydrides.

The reaction is carried out in the presence of bases in organic solventswhich do not interfere with the reaction. Suitable bases are, above all,organic bases, such as, for example, N,N-dimethylaniline ortriethylamine. Examples of possible organic solvents which do notinterfere with the reaction are halogenated hydrocarbons, such as, forexample, methylene chloride or chloroform, or tertiary amides, such as,for example, dimethylformamide or dimethylacetamide. The reaction isappropriately carried out at room temperature.

If in the general formula III the radical R₁ represents a group whichcan be easily removed again, its introduction into the amino group canbe effected in the manner known from peptide chemistry foramino-protective groups (compare the book mentioned below by Schroderand Lubke, The Peptides, volume 1 (1965), page 3). If such a group is,for example, triphenylmethyl, its introduction can be effected withtriphenylchloromethane, the reaction appropriately being carried out inan organic solvent, such as, for example, halogenated hydrocarbons, inthe presence of bases.

Chloroform and methylene chloride have proved particularly suitablehalogenated hydrocarbons here. Bases which can be mentioned are, inparticular, tertiary amines, such as, for example, triethylamine orN-methylmorpholine.

It is appropriate, not only in the manufacture of the carboxylic acidIII which contans a group ##STR32## in the syn-position, but also in allother reactions, to use reaction conditions which are as mild and gentleas possible, such as are known to the expert, from the literature, forreactions with syn-compounds and β-lactams, such as, for example, noelevated temperatures, reaction times which are as short as possible, nosubstantial excesses of an acid reactant and the like, in order to avoidany possible flipping over of the oxime group into the anti-form and asplitting of the β-lactam ring.

The reactive derivatives of the carboxylic acids of the general formulaIII ##STR33## which are employed, according to the invention, for theacylation reaction (a) and which are capable of amide formation can beobtained from the carboxylic acids by processes which are known from theliterature. Examples of reactive derivatives which may be mentioned arethe activated esters, such as, for example, p-nitrophenyl esters ortrichlorophenyl esters, azides or anhydrides. A preferred process foractivating the carboxyl group consists in converting it into a symmetricanhydride. The processes for the manufacture of symmetric anhydrides areknown from the literature and correspond to the methods generally usedin peptide chemistry. For example, the inner anhydrides, which aresubsequently reacted with the aminocephemcarboxylic acids of the formulaII in organic solvents, are obtained from the carboxylic acids of thegeneral formula III using condensing agents, such as, for example,N,N-disubstituted carbodiimides, such as, for example,dicyclohexylcarbodiimide.

The manufacture of the compounds of the general formula I by acylatingcompounds of the formula II with the carboxylic acids of the formula IIIcan be carried out under variable experimental conditions, for exampleusing various solvents. Examples of suitable solvents are organicsolvents, such as, for example, halogenated hydrocarbons, for examplemethylene chloride or chloroform, but also water or mixtures of waterand organic solvents, which are mixed intensively with water. In orderto carry out the reaction well, it is appropriate to dissolve theaminolactam derivatives of the formula II.

If lactams of the general formula II in which R₃ represents one of theester groups defined above are used, the reaction is preferably carriedout in organic solvents, in which most of the esters are readilysoluble. Examples of such solvents which may be mentioned arehalogenated hydrocarbons, such as, for example, methylene chloride orchloroform, but also tertiary amides, such as, for example,dimethylformamide or dimethylacetamide.

The ester groups listed above under R₃ include on the one hand thosesuch as, for example, are known from peptide chemistry ascarboxyl-protective groups which can be easily split off (compare, forexample, E. Schroder and K. Lubke, The Peptides, volume 1, AcademicPress, New York and London, 1965, page 52). However, they preferablyinclude ester groups, the use of which can be therapeuticallyadvantageous in the administration of the end products. In this casealso the restrictions can be somewhat flexible, since, for example, abenzhydryl ester is therapeutically usable and at the same time can alsoserve as a protective group.

If lactams of the general formula II in which R₃ represents hydrogen areused, the compounds must be dissolved, with the addition of bases.

Suitable bases which can be used for the solution are inorganic ororganic bases. Thus, tertiary amines, such as triethylamine,N,N-dimethylaniline or N-methylmorpholine, have proved particularlysuitable for the preparation of solutions in organic solvents, andalkali metal bicarbonates, such as sodium bicarbonate or potassiumbicarbonate, and tertiary amines have proved particularly suitable forthe preparation of aqueous solutions. In general, the bases are added inat least stoichiometric amount, relative to the desired reaction. Anexcess of base of, for example, about 0.1 to 2, in particular about 0.2to 0.8, moles can be advantageous.

In the case of compounds of the formula II which are sensitive towardsbases, depending on the course of the reaction, the pH can be keptconstant at about 4 to 8, preferably 6 to 7, by continuously adding thebase.

The aminolactam derivatives of the formula II can be dissolved in a widetemperature range. However, appropriately it should not exceed atemperature of about 40° C. In the case of derivatives which aresensitive towards bases, it is advisable, however, to choose atemperature range from about 0° to 15° C.

The activated derivatives of the carboxylic acids of the general formulaIII are added to the lactams of the formula II, which are present insolution or appropriately in suspension. The reaction is carried out ina manner which is in itself known. If water or mixtures of water andorganic solvents are used as the reaction medium, it is advisable tomaintain the temperature in a range from about -5° to +10° C. If organicsolvents are used, it is also possible to carry out the acylation attemperatures up to about 65° C., preferably at room temperature.

In order to carry out the reaction better, the activated carboxylic acidderivatives of the formula III are taken up in a solvent which does notinterfere with the reaction and are introduced in dilute form. If theacylation is carried out in an aqueous medium, it is possible to use,for example, anhydrous ketones, such as acetone or methyl ethyl ketone,or, with intensive stirring, ethers, such as, for example, diethyl etheror diisopropyl ether, as solvents for the activated carboxylic acidderivatives.

If the acylation is carried out in a non-aqueous medium, it is advisableto use the same solvent for diluting the acid derivatives as is used forthe acylation.

In order to achieve higher yields, the activated acid derivatives of theformula III are employed in an at least stoichiometric amount. An excessof about 5-25% can prove appropriate.

Compounds of the formula I can also be obtained by interchanging thestages described above of oxidation of lactams of the formula XI to givethe sulfoxide or sulfone of the formula II and acylation with carboxylicacids of the formula III. Thus, it is possible to first acylate thelactams of the formula XI, wherein A, R₃ and R₄ have the meaningindicated above, but R₃ cannot be hydrogen, with carboxylic acids of theformula III in which the radicals R₁ and R₂ have the abovementionedmeaning, to give the cephem compounds of the formula IV. The acylationis carried out in the manner described for the reaction of compounds ofthe general formula II and III. The subsequent oxidation to thesulfoxide or sulfone of the general formula I can be carried out underthe reaction conditions indicated for the oxidation of the lactams ofthe general formula XI to give the compounds of the formula II.Protection of the 7-amino group is thereby superfluous since, because ofthe preceding step of acylation with acids of the formula III, the7-amino group is no longer attacked. The oxidation of compounds of thegeneral formula IV predominantly gives sulfoxides with the Sconfiguration, which may also contain R sulfoxides which can then beseparated off in the manner described above.

Compounds of the formula IV in which A denotes --CH₂ Y, wherein Yrepresents the radical of a S-nucleophilic or N-nucleophilic compoundwith the meanings indicated above, can be manufactured in a manner whichis in itself known, for example by reacting compounds of the formula IVin which R₃ represents hydrogen or a cation and the radical A denotes,for example, --CH₂ --OCOCH₃ or --CH₂ -- halogen with a compoundcontaining a S-nucleophilic or N-nucelophilic radical, in particularwith S-nucleophilic compounds of the formula HSR₅, hydrazoic acid aswell as optionally substituted pyridine, quinoline or isoquinolinecompounds.

The reaction can be carried out by reacting one mole of a compound ofthe formula IV, in which the radicals R₁, R₂ and R₄ have the meaningindicated above, R₃ represents hydrogen or a cation and A represents,for example, acetoxymethyl, with at least one mole of a compoundcontaining the nucleophilic radical Y, in particular of the compoundsmentioned above as preferred, in a solvent which does not interfere withthe reaction.

An excess of the nucleophiles, in particular of the thiol, pyridine,quinoline or isoquinoline component, has an advantageous effect on theyield. Should small amounts of the corresponding anti-compound beobtained here, they can be removed in the customary manner, for exampleby recrystallization.

Examples of solvents which do not interfere with the reaction are water,acetone, chloroform, nitrobenzene, methylene chloride, ethylenechloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran,dimethylsulfoxide or any other solvents which do not have an adverseeffect on the reaction. Strongly polar solvents are favorable,preferably water. Of the solvents, the hydrophilic solvents, preferablyacetone, methanol, ethanol, dimethylformamide and dimethylsulfoxide, canalso be used in mixtures with water.

The reaction is carried out in a pH range from 5 to 8, preferably at theneutral pH value.

If the compound IV (in which R₃ =hydrogen and A is, for example,acetoxymethyl or chloromethyl) or the nucleophilic compound, inparticular HS--R₅, is used in the free form, the reaction is preferablycarried out in the presence of a base, for example an inorganic base,such as an alkali metal hydroxide, alkali metal carbonate or alkalimetal bicarbonate, such as, for example, sodium bicarbonate or potassiumbicarbonate, an organic base, such as a trialkylamine, or a tertiaryammonium base. The compounds of the formula IV and the HS--R₅ can alsobe employed directly in the form of their salts, preferably the sodiumor potassium salts.

The reaction temperature can be varied within a wide range. As a rule,the reaction is carried out at room temperature or the mixture is warmedup to the reflux temperature of the solvents or solvent mixtures used,but appropriately not above about 80° C.

Compounds of the formula IV in which R₃ represents hydrogen or a cationcan be converted into an ester (R₃ =an ester group) by reacting such anacid or salt of the formula IV with a compound of the formula R₃ -B,wherein B represents a leaving group, such as, for example, halogen, forexample chlorine, bromine or iodine, or a methylsulfonyloxy or tosyloxygroup, in a manner which is in itself known in a pH range from 5-8,preferably at the neutral pH value.

The isolation of the compounds of the formula I from the reaction mediumcan be effected by methods which are in themselves known, which dependon the solubility of the resulting compounds, and in general leads toamorphous or crystalline end products.

Thus, for example, the reaction products can be taken up in water ororganic solvents, if appropriate after concentrating or evaporating thesolution, and after appropriate purification operations, such as, forexample, filtration, trituration or centrifugation, can be precipitatedin the form of the free carboxylic acids (R₃ =hydrogen) by addingmineral acids, appropriately in an approximately stoichiometric amount,to the clarified reaction mixture. Suitable mineral acids are, inparticular, dilute acids, such as dilute hydrochloric acid or sulfuricacid. It is also possible to use very low-molecular weight organicacids, such as, for example, formic acid or trifluoroacetic acid, oralso arylsulfonic acids, such as, for example, toluenesulfonic acids ornaphthalenesulfonic acids. Lyophilization of the solution canoccasionally also be appropriate.

If symmetric anhydrides of the carboxylic acids of the formula III havebeen used as the starting component, the carboxylic acid constituentliberated during the acylation must be separated by customaryexperimental methods, which depend, for example, on its solubility,crystallinity or ease of extraction.

If desired, protective groups which have been introduced forintermediate protection of the amino group of the aminothiazole radicalcan be removed by processes which are known from the literature, such asare described, for example, for peptide chemistry. For example, if R₁represents a triphenylmethyl group, the splitting off is effected in anacid medium. Mixtures of formic acid and water, in particular mixturesof water and formic acid in the ratio 1:1 to 4:1, have proved suitable.

The compounds of the formula I containing a free amino and carboxylgroup can be isolated by known experimetal methods, for example in thecase where a triphenylmethyl group is split off as triphenylcarbinol, byfiltering off the triphenylcarbinol and then concentrating the solution.

Esters obtained in the reaction according to the invention, the estergroup of which has a protective group for the carboxyl group, such as,for example, p-methoxybenzyl, p-nitrobenzyl or tert.-butyl esters, can,if desired, also be converted into the free carboxylic acids of theformula I in a manner which is known from the literature. However, asalready mentioned, it is also possible to retain for therapeutic useester groups which also serve as carboxyl-protective groups, such as,for example, benzhydryl esters.

Compounds of formula I having a free α-oxime group (R₂ =hydrogen) can beprepared by the process of the invention, for example by exchange of Yin the definition of acetoxy and X=S in compounds of formula I in whichR₂ denotes hydrogen with subsequent oxidation to obtain the sulfoxideX=SO), or by splitting off a group R₂ having the character of aprotective group from compounds of formula I in known manner by acidhydrolysis or hydrogenolysis, groups of this type being, for exampletert.butyloxycarbonyl, dibenzyl, carbobenzyloxy, formyl,trichloroethoxycarbonyl, 2-tetra-hydropyranyl, preferablytriphenylmethyl.

For acid hydrolysis there may be used, for example, formic acid,trifluroracetic acid or acetic acid, which can be used either inanhydrous form or in aqueous solutions.

Preferred agents for acid hydrolysis are anhydrous trifluoroacetic acid,aqueous formic acid or acetic acid if tert. butoxycarbonyl ortriphenylmethyl shall be split off. Dibenzyl or carbobenzyloxy, forexample, are preferably split off by catalytic hydrogenation agents.

If R₂ denotes chloroacetyl, this may be split off also with thiourea,preferably in a neutral or acid medium (cf. JACS 90 (1968), page 4508).

Simultaneously with R₂, a radical R₁ denoting a protective group can besplit off by acid hydrolysis, hydrogenolysis or with thiourea. It is thesame with the radical R₃ provided it can be eliminated by hydrolysis orhydrogenolysis. In the case of compounds containing radicals R₁, R₂ andR₃ having the function of protective groups which can be split off indifferent manner only, for example by hydrolysis and hydrogenolysis orwith different hydrolysis agents, these methods should be appliedsuccessively.

The resulting acids of the formula I can be converted into theirphysiologically acceptable salts, in particular into alkali metal salts,such as, for example, the sodium salts, or into salts with organicbases, preferably tertiary amines, such as, for example, the procainesalt.

The conversion into salts can be effected in a manner which is in itselfknown by reacting a carboxylic acid of the general formula I with thedesired base, for example with sodium bicarbonate, or the sodium saltsof organic carboxylic acids, such as, for example, sodium acetate,sodium propionate, sodium hexanoate or sodium 2-ethyl-hexanoate, orpotassium acetate.

It is also possible to isolate salts directly from the reactionsolution, for example by precipitation with suitable organic solvents orby lyophilization.

Compounds of the formula I in which R₃ represents an ester group, inparticular a physiologically acceptable ester, can be obtained directlyby using the appropriately esterified starting material of the formulaII, or they can be obtained by subsequent esterification of compounds ofthe formula I in which the carboxyl group is present in the free form oras a salt, by processes which are known from the literature. Because itis easier to carry out, subsequent esterification can be advantageousfor the manufacture of physiologically acceptable esters and a variationof the ester group.

For example, esters are obtained by subsequent reaction when the salts,preferably the triethylammonium salts or the alkali metal salts,preferably the sodium salts, are reacted with reactive halogenoalkylcompounds, such as, for example, chloroalkyl, bromoalkyl or iodoalkylcompounds, or trialkylammoniumalkyl compounds, in particular thecorresponding chloromethyl, bromomethyl, iodoethyl ortriethylammoniummethyl compounds. Examples of reactive halogenoalkylcompounds which can be used are halogenomethoxycarbonyl compounds, suchas chloromethyl acetate, chloromethyl propionate or chloromethylpivalate, or the ω-halogenomethyl ketones, such as, for example,ω-bromoacetophenone, chloroacetone or ω-bromoacetophenone substituted inthe aryl nucleus, such as, for example, in the phenyl nucleus, such as,for example, 5-sulfamyl-4-chloro-ω-bromoacetophenone, but alsohalogenoalkyl-carboxylic acid derivatives, in particular thehalogenomethyl-carboxylic acid derivatives, such as chloroacetic acid,bromoacetic acid and bromoacetic acid esters, such as, for example, thelow-molecular alkyl esters and optionally the benzyl esters, such as thep-methoxybenzyl ester. Halogenomethyl ketones in which the 2-alkyl groupis monosubstituted or polysubstituted by alkoxycarbonyl, oximino, oxidoor alkoximino radicals, such as, for example,1-chloro-(3-methoxyimino-3-carbethoxy)-acetone or1-bromo-3-methoxyimino-3-carbethoxyacetone, but alsobromo-3-oxido-3-carbethoxyacetone, have proved suitable reactivehalogenomethyl derivatives.

Further reactive halogenoalkyl derivatives which may be mentioned arethe alkyl iodides, such as, for example methyl iodide, ethyl iodide orisopropyl iodide, and the corresponding bromides.

The reaction with diazoalkanes, such as, for example, diazomethane ordiazoethane, but also diarylmethyldiazomethane, such as, for example,diphenyldiazomethane, may furthermore be mentioned for the manufactureof optionally substituted esters.

A further esterification method consists in reacting the alkali metalsalts, preferably in alcohol, such as, for example, methanol, with alkylsulfochlorides, such as, for example, methyl sulfochloride.

The reaction of the salts of the cephem compounds of the formula I withalkyl halides is appropriately carried out in a solvent which does notinterfere with the reaction, such as, for example, dimethylformamide ordimethylacetamide, or also dimethylsulfoxide. The reaction can becarried out within a wide temperature range, for example at 0° to 80°C., but preferably at 30°-50° C., depending on the activity of thehalogenoalkane.

In order to achieve good yields, the halogenoalkane is employed in an atleast equimolar amount. An excess of up to 5 equivalents has sometimesproved favorable.

Depending on the desired end product, the process steps (α) to (δ) whichare possible according to the invention can be combined with oneanother, it frequently being possible to rearrange the sequence. Theserearrangement possibilities of the reaction steps, which areself-evident to any expert, also belong to the subject of the invention.

If R₄ is present in the form of one of the groups described above whichcan be converted into lower alkoxy, preferably methoxy, this conversioncan be carried out in a manner which is known from the literature(compare, for example, German Offenlegungsschrift No. 2,440,790).

The compounds of the general formula I according to the invention arevaluable chemotherapeutic agents which possess a very powerfulantimicrobial action against Gram-positive and Gram-negative bacteria,have an unexpectedly good action against penicillinase-formingStaphylococci and in some cases also have a fungistatic activity. Thehigh activity of the sulfoxides with the S configuration must beregarded as particularly surprising.

The compounds of the general formula I are distinguished, for example,by a considerable antimicrobial activity against a number of bacteriaagainst which the known cephalosporins are scarcely active.

Since the compounds of the formula I furthermore exhibit favorabletoxicological and pharmacokinetic properties, they are valuableantimicrobial active compounds for the treatment of infectious diseases.

The invention thus also relates to medicinal formulations for thetreatment of microbial infections, which are characterized in that theycontain one or more of the compounds according to the invention.

The products according to the invention can also be used in combinationwith other active compounds, for example from the series of penicillins,aminoglycosides, cephalosporins or compounds which influence thesystematics of bacterial infections, such as, for example, antipyreticagents, analgesic agents or antiphlogistic agents.

The compounds of the general formula I can be administered orally,intramuscularly or intravenously.

Medicinal formulations which contain on or more compounds of the generalformula I as the active compound can be prepared by mixing thecompound(s) of the general formula I with one or more pharmacologicallyacceptable excipients or diluents, such as, for example, fillers,emulsifiers, lubricants, flavor-correcting agents, dyestuffs or buffersubstances, and converting the mixture into a suitable galenicformulation form, such as, for example, tablets, dragees, capsules or asolution or suspension suitable for parenteral administration. Examplesof excipients or diluents which may be mentioned are tragacanth,lactose, talc, agar-agar, polyglycols, ethanol and water. Suspensions orsolutions in water can preferably be used for parenteral administration.It is also possible to administer the active compounds as such, withoutexcipients or diluents, in a suitable form, for example in capsules.

Suitable doses of the compounds of the general formula I are about 0.4to 20 g/day, preferably 0.5 to 4 g/day, for an adult having a bodyweight of about 60 kg. Individual doses or, in general, multiple dosesmay be administered, it being possible for the individual dose tocontain the active compound in an amount of about 50 to 1,000 mg,preferably 100 to 500 mg.

In addition to the compounds described in the embodiment examples, it isalso possible, for example, to manufacture according to the inventionthe following compounds given in the table, the substituents R₁, R₂, R₃,R₄ and A indicated for the particular compound relating to the basicstructure of the general formula XII ##STR34## in which the group --OR₂is in the syn-position and SO is in the R or S configuration.

      R.sub.1 R.sub.2 R.sub.3 R.sub.4 A       H H H H CH.sub.3 H H H H CH.sub.2 OCOCH.sub.3 H H H OCH.sub.3 CH.sub.2     OCOCH.sub.3 H H H H CH.sub.2 OH H H H H CH.sub.2 OCOC.sub.2 H.sub.5 H H     H H CH.sub.2 OCOC.sub.4 H.sub.9 H H H H CH.sub.2 OCONH.sub.2 H H H H     CH.sub.2 OCONHCH.sub.3 H H H H CH.sub.2 SCOCH.sub.3 H H H H CH.sub.2     SCOC.sub.2 H.sub.5 H H H H CH.sub.2      SCOCH(CH.sub.3).sub.2 H H H OCH.sub.3 CH.sub.2SCOCH.sub.3 H H H H Cl H     H H H OCH.sub.3 H H H H CH.sub.2 Cl H H H H CH.sub.2 F H H H H OC.sub.4     H.sub.9 H CH.sub.3 H OCH.sub.3 CH.sub.3 H CH.sub.3 H OCH.sub.3 CH.sub.2     OH H CH.sub.3 H OCH.sub.3 CH.sub.2 OCOCH.sub.3 H CH.sub.3 H H CH.sub.2     OCOC.sub.2 H.sub.5 H CH.sub.3 H H CH.sub.2 OCOC.sub.4 H.sub.9 H CH.sub.3     H H CH.sub.2 OCONH.sub.2 H CH.sub.3 H H CH.sub.2 OCONHC.sub.2 H.sub.5 H     CH.sub.3 H H CH.sub.2 SCOCH.sub.3 H CH.sub.3 H H CH.sub.2 SCOC.sub.2     H.sub.5      H CH.sub.3 H H     ##STR35##       H CH.sub.3 H H CH.sub.2 SCOCH.sub.2 C.sub.6 H.sub.5  H CH.sub.3 H H      ##STR36##      H CH.sub.3 H H     ##STR37##      H CH.sub.3 H H     ##STR38##       H CH.sub.3 H H Cl H CH.sub.3 H H OCH.sub.3 H CH.sub.3 H H CH.sub.2 CL     H CH.sub.3 H H OC.sub.4 H.sub.9 H CH.sub.3 H OCH.sub.3 OCH.sub.3 H     CH.sub.3 CH.sub.3 H CH.sub.1 OCOCH.sub.3 H CH.sub.3 C.sub.4 H.sub.9 H     CH.sub.2 OCOCH.sub.3 H CH.sub.3 CH.sub.2 CHCH.sub.2 H CH.sub.2      OCOCH.sub.3      H CH.sub.3     ##STR39##      H CH.sub.2 OCOCH.sub.3  H CH.sub.3 C.sub.8 H.sub.17 H CH.sub.2      OCOCH.sub.3 H CH.sub.3 C.sub.12 H.sub.25 H CH.sub.2 OCOCH.sub.3 H     CH.sub.3 CH.sub.2 CCH H CH.sub.2 OCOCH.sub.3 H CH.sub.3 CH.sub.2     CCl.sub.3 H CH.sub.2 OCOCH.sub.3 H CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 H     CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR40##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR41##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR42##      H CH.sub.2 OCOCH.sub.3  H CH.sub.3 CH(C.sub.6 H.sub.5).sub.2 H CH.sub.2     OCOCH.sub.3      H CH.sub.3     ##STR43##      H CH.sub.2 OCOCH.sub.3  H CH.sub.3 CH.sub.2 CO.sub.2 H H CH.sub.2     OCOCH.sub.3 H CH.sub.3  CH.sub.2CO.sub.2 C.sub.2 H.sub.5 H CH.sub.2     OCOCH.sub.3      H CH.sub.3     ##STR44##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR45##      H CH.sub.2 OCOCH.sub.3  H CH.sub.3 CH.sub.2 CONH.sub.2 H CH.sub.2     OCOCH.sub.3 H CH.sub.3 CH.sub.2 CONHCH.sub.3 H CH.sub.2 OCOCH.sub.3 H     CH.sub.3 CH.sub.2 CONHC.sub.4 H.sub.9 H CH.sub.2 OCOCH.sub.3  H CH.sub.3      ##STR46##      H CH.sub.2 OCOCH.sub.3  H CH.sub.3 CH.sub.2 OCOCH.sub.3 H CH.sub.2     OCOCH.sub.3      H CH.sub.3     ##STR47##      H CH.sub.2 OCOCH.sub.3  H CH.sub.3 CH.sub.2 COC.sub.6 H.sub.5 H     CH.sub.2 OCOCH.sub.3 H  CH.sub.3 CH.sub.2OCOC.sub.6 H.sub.5 H CH.sub.2     OCOCH.sub.3      H CH.sub.3     ##STR48##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR49##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR50##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR51##      H CH.sub.2 OCOCH.sub.3      H CH.sub.3     ##STR52##      H CH.sub.2 SCOCH.sub. 3  H CH.sub.3 CH.sub.2 OCOC(CH.sub.3).sub.3 H     CH.sub.2 SCOCH.sub.3 H CH.sub.3 Si(CH.sub.3).sub.3 H CH.sub.2      OCOCH.sub.3 H CH.sub.3 CH.sub.2 OCOC(CH.sub.3).sub.3 H Cl H CH.sub.3     CH.sub.2 OCOC(CH.sub.3).sub.3 H OCH.sub.3 H CH.sub.3 CH.sub.2      OCOC(CH.sub.3).sub.3 H CH.sub.2OCONH.sub.2 H C.sub.2      H.sub.5 H OCH.sub.3 CH.sub.2 OCOCH.sub.3 H C.sub.2 H.sub.5 H H CH.sub.2     OCOC(CH.sub.3).sub.3 H C.sub.2 H.sub.5 H H CH.sub.2 OH H C.sub.2 H.sub.5     H H CH.sub.2OCONH.sub.2  H C.sub.2      H.sub.5 H H     ##STR53##       H C.sub.2 H.sub.5 H H CH.sub.2SCOCH.sub.3 H C.sub.2 H.sub.5 H H     CH.sub.2SCOC.sub.4 H.sub.9 H C.sub.2 H.sub.5 H H Cl H C.sub.2 H.sub. 5 H     H OCH.sub.3  H C.sub.2      H.sub.5 H H     ##STR54##       H C.sub.2      H.sub.5 H H     ##STR55##       H C.sub.2 H.sub.5 H H CH.sub.3 H C.sub.2 H.sub.5 C(CH.sub.3).sub.3 H     CH.sub.2 OCOCH.sub.3 H C.sub.2 H.sub.5 CH(C.sub.6 H.sub.5).sub.2 H     CH.sub.2 OCOCH.sub.3 H C.sub.2 H.sub.5 CH.sub.2 OCOC(CH.sub.3).sub.3 H     CH.sub.2 OCOCH.sub.3  H C.sub.2      H.sub.5     ##STR56##      H CH.sub.2 OCOCH.sub.3  H C.sub.2      H.sub.5     ##STR57##       H CH.sub.2 OCOCH.sub.3  H C.sub.2 H.sub.5 CH.sub.2CO.sub.2 H H     CH.sub.2 OCOCH.sub.3 H C.sub.2 H.sub.5 CH.sub.2 CCl.sub.3 H CH.sub.3 H     n-C.sub.3 H.sub.7 H OCH.sub.3 OCH.sub.3 H n-C.sub.3      H.sub.7 H H OCH.sub.3 H n-C.sub.3 H.sub.7 H H Cl H n-C.sub.3 H.sub.7 H     H CH.sub.2SCOCH.sub.3 H n-C.sub.3 H.sub.7 H H CH.sub.2OCONH.sub.2  H     n-C.sub.3      H.sub.7 H H     ##STR58##       H n-C.sub.3 H.sub.7 C(CH.sub.3).sub.3 H CH.sub.2 OCOCH.sub.3  H     n-C.sub.3      H.sub.7     ##STR59##      H CH.sub.2 SCOC.sub.4 H.sub.9  H n-C.sub.3 H.sub.7 CH.sub. 2      OCOC(CH.sub.3).sub.3 H CH.sub.2 OCOCH.sub.3 H i-C.sub.3 H.sub.7 H     OCH.sub.3 CH.sub.2 OCOCH.sub.3 H i-C.sub.3 H.sub.7 H H CH.sub.2 OH H     i-C.sub.3 H.sub.7 H H Cl H i-C.sub.3 H.sub.7 H H OCH.sub.3 H i-C.sub.3     H.sub.7 H H CH.sub.2 OCONH.sub.2 H i-C.sub.3 H.sub.7 H H CH.sub.2     SCOCH.sub.3 H i-C.sub.3 H.sub.7 C(CH.sub.3).sub.3 H CH.sub.2 OCOCH.sub.3     H i-C.sub.3 H.sub.7 CH.sub.2 OCOC(CH.sub.3).sub.3 H CH.sub.2 OCOCH.sub.3     H n-C.sub.4 H.sub.9 H OCH.sub.3 CH.sub.2 OCOCH.sub.3 H n-C.sub.4 H.sub.9     H H CH.sub.2 SCOCH.sub.3 H n-C.sub.4 H.sub.9 H H CH.sub.2 OCONH.sub.2 H     n-C.sub.4 H.sub.9 H H CH.sub.2 OH H n-C.sub.4 H.sub.9 H H Cl H n-C.sub.4     H.sub.9 H H OCH.sub.3 H n-C.sub.4 H.sub. 9 H H CH.sub.2 Cl H n-C.sub.4     H.sub.9 H H OCH.sub.2CH.sub.2 OCH.sub.3 H n-C.sub.4                      C      H.sub.9 H H OCH.sub.2HCH.sub.2 H n-C.sub.4      H.sub.9 H H O(CH.sub.2).sub.2 On-C.sub.4 H.sub.9 H i-C.sub.4 H.sub.9 H     H CH.sub.2 OCOCH.sub.3 H i-C.sub.4 H.sub.9 H H C.sub.2 SCOCH.sub.3 H     CH.sub.2CHCH.sub.2 H H CH.sub.2 OH H CH.sub.2CHCH.sub.2 H H CH.sub.2     OCOCH.sub.3 H CH.sub.2CHCH.sub.2 H H CH.sub.2      SCOCH.sub.3 H CH.sub.2CHCH.sub.2 H OCH.sub.3 CH.sub.2 OCOCH.sub.3 H     CH.sub.2CHCH.sub.2 H OCH.sub.3 CH.sub.2SCOCH.sub.3 H CH.sub.2CHCH.sub.2     H H CH.sub.2      OCONH.sub.2 H CH.sub.2CHCH.sub.2 H H Cl H CH.sub.2CHCH.sub.2 H H     OCH.sub.3 H CH.sub.2CHCH.sub.2 H H CH.sub.2 Cl H CH.sub.2CHCHCH.sub.3 H     H CH.sub.2 OH H CH.sub.2CHCHCH.sub.3 H H CH.sub.2                        C      OCOCH.sub.3 H CH.sub.2CH H H CH.sub.2 OCOCH.sub.3 H CH.sub.2 CO.sub.2     CH.sub.3 H H CH.sub.2 OH H CH.sub.2 CO.sub.2 CH.sub.3 H H CH.sub.2     OCOCH.sub.3 H CH.sub.2 CO.sub.2 CH.sub.3 H H CH.sub.3 H CH.sub.2     CO.sub.2 CH.sub.3 H H CH.sub.2 OCH.sub.3 H CH.sub.2 CO.sub.2 CH.sub.3 H     H OCH.sub.3 H CH.sub.2 CO.sub.2 CH.sub.3 H H Cl H CH.sub.2 CO.sub.2     C.sub.2 H.sub.5 H H CH.sub.2OCOCH.sub.3 H CH.sub.2CO.sub.2 C.sub.2     H.sub.5 H H CH.sub.3      H     ##STR60##      H H CH.sub.2 OCOCH.sub.3      H     ##STR61##      H H CH.sub.2 OCOCH.sub.3  H CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3 H H     CH.sub.2 OCOCH.sub.3      H     ##STR62##      H H CH.sub.2 OCOCH.sub.3 H CH.sub.2 CO.sub.2 H H H CH.sub.2 OCOCH.sub.3     H CH.sub.2 CO.sub.2 H H OCH.sub.3 CH.sub.2 OCOCH.sub.3 H CH.sub.2     CO.sub.2 H H H CH.sub.3 H CH.sub.2 CO.sub.2 H H H CH.sub.2 OH H CH.sub.2     CO.sub.2 H H H CH.sub.2 SCOCH.sub.3 H CH.sub.2 CO.sub.2 H H H CH.sub.2     OCONH.sub.2 H CH.sub.2 CO.sub.2 H H H CH.sub.2 Cl H CH.sub.2 CO.sub.2 H     H H OCH.sub.3 H CH.sub.2 CO.sub.2 H H OCH.sub.3 Cl      H     ##STR63##      H H CH.sub.2 OCOCH.sub.3      H     ##STR64##      H H CH.sub.2 OCOCH.sub.3  H CH.sub.2CH.sub.2 CO.sub.2 H H H CH.sub.2     OCOCH.sub.3 H CH.sub.2 CONH.sub.2 H H CH.sub.2 OCOCH.sub.3 H CH.sub.2     CONHCH.sub.3 H H CH.sub.2 OCOCH.sub.3      H     ##STR65##      H H CH.sub.2 OCOCH.sub.3  H CH.sub.2 CONHC.sub.4 H.sub.9 H H CH.sub.2     OCOCH.sub.3      H     ##STR66##      H H CH.sub.2 OCOCH.sub.3      H     ##STR67##      H H CH.sub.2 OCOCH.sub.3  H CH.sub.2 SO.sub.2 NH.sub.2 H H CH.sub.2     OCOCH.sub.3 H CH.sub.2 SO.sub.3 H H H CH.sub.2 OCOCH.sub.3 H CH.sub.2     CH.sub.2 OH H H CH.sub.2 OCOCH.sub.3 H CH.sub.2 CH.sub.2 OCH.sub.3 H H     CH.sub.2 SCOCH.sub.3 H CH.sub.2OCOCH.sub.3 H H CH.sub.2 OCOCH.sub.3 H     CH.sub.2CH.sub.2 SO.sub.3 C.sub.2 H.sub.5 H H CH.sub.2 OCOCH.sub.3  H      ##STR68##      H H CH.sub.2 OCOCH.sub.3      H     ##STR69##      H H CH.sub.2 OCOCH.sub.3      H     ##STR70##      H H CH.sub.2 OCOCH.sub.3      H     ##STR71##      H OCH.sub.3 CH.sub.2 OCOCH.sub.3      H     ##STR72##      H H      ##STR73##      H     ##STR74##      H H CH.sub.2 OCOCH.sub.3      H     ##STR75##      H H CH.sub.2 OCOCH.sub.3      H     ##STR76##      H H CH.sub.2 OCOCH.sub.3      H     ##STR77##      H H CH.sub.2 OCOCH.sub.3      H     ##STR78##      H H CH.sub.2 OCOCH.sub.3      H     ##STR79##      H H CH.sub.2 OCOCH.sub.3      H     ##STR80##      H H CH.sub.2 OCOCH.sub.3      H     ##STR81##      H H CH.sub.2 OCOCH.sub.3      H     ##STR82##      H H CH.sub.2 OCOCH.sub.3      H     ##STR83##      H H CH.sub.2 OCOCH.sub.3      H     ##STR84##      H H CH.sub.2 OCOCH.sub.3      H     ##STR85##      H H CH.sub.2 OCOCH.sub.3  H COCH.sub.3 H H CH.sub.2 OCOCH.sub.3 H     COCH.sub.2 Cl H H CH.sub.2 Cl H COCHCl.sub.2 H H CH.sub.2 SCOCH.sub.3  H      ##STR86##      H H CH.sub.2 OCOCH.sub.3      H     ##STR87##      H H CH.sub.2 OCOCH.sub.3  H SO.sub.2CH.sub.3 H H CH.sub.2 OCOCH.sub.3     H      ##STR88##      H H CH.sub.2 OCOCH.sub.3      H     ##STR89##      H OCH.sub.3 Cl      H     ##STR90##      H H CH.sub.2 OCOCH.sub.3      H     ##STR91##      H H CH.sub.2 OCOCH.sub.3      H     ##STR92##      H H CH.sub.2 OCOCH.sub.3  H CH.sub.2CHCHCO.sub.2 H H H CH.sub.2     OCOCH.sub.3      H H H H     ##STR93##       H C.sub.2      H.sub.5 H H     ##STR94##      H CH.sub.3 H H     ##STR95##      H CH.sub.3 H H     ##STR96##      H CH.sub.3 H OCH.sub.3     ##STR97##       H CH.sub.2 CO.sub.2      H H H     ##STR98##      H CH.sub.3 H H     ##STR99##       H nC.sub.4      H.sub.9 H H     ##STR100##      H CH.sub.2CHCH.sub.2 H H     ##STR101##      H CH.sub.3 H H     ##STR102##      H CH.sub.3 H H     ##STR103##      H     ##STR104##      H H      ##STR105##       H C.sub.2      H.sub.5 H H     ##STR106##      H H H H     ##STR107##      H     ##STR108##      H H      ##STR109##      H CH.sub.3 H H     ##STR110##      H CH.sub.3 H H     ##STR111##      H CH.sub.3 H H     ##STR112##       H CH.sub.3 CH.sub.2      OCO(CH.sub.3).sub.3 H     ##STR113##      H CH.sub.3     ##STR114##      H      ##STR115##      H CH.sub.3     ##STR116##      H      ##STR117##       HCO H H H CH.sub.2 OCOCH.sub.3 COCH.sub.3 H H H CH.sub.2 OCOCH.sub.3     COCH.sub.2 Cl CH.sub.3 H H CH.sub.2 OCOCH.sub.3 COCH.sub.2 βr     CH.sub.3 H H CH.sub.2 OCOCH.sub.3 nC.sub.4 H.sub.g CO CH.sub.3 H     OCH.sub.3 CH.sub.2 OCOCH.sub.3 COCCl.sub.3 CH.sub.3 H H CH.sub.2     OCOCH.sub.3      ##STR118##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR119##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR120##      CH.sub.3 H H CH.sub.2 SCOCH.sub.3      ##STR121##      H H H CH.sub.2 OCOCH.sub.3      ##STR122##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR123##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR124##      C.sub.2 H.sub.5 H H CH.sub.2 Cl      ##STR125##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR126##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3  COOC(CH.sub.3).sub.3 CH.sub.3 H H     CH.sub.2 OCOCH.sub.3 C(C.sub.6 H.sub.5).sub.3 CH.sub.2 CO.sub.2 C.sub.2     H.sub.5 H H CH.sub.2 OCOCH.sub.3 COC.sub.6 H.sub.13 C.sub.2 H.sub.5 H H     CH.sub.2 OCOCH.sub.3      ##STR127##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR128##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR129##      CH.sub.3 H H CH.sub.2SCOCH.sub.3  COCH.sub.2      Cl CH.sub.3 H H     ##STR130##       COOCH.sub.2 CCl.sub.3 CH.sub.3 H H CH.sub.2 OCOCH.sub.3 COOCH.sub.2     CCl.sub.3 H H H CH.sub.2 OCOCH.sub.3 COOCH.sub.2 CCl.sub.3 C.sub.2     H.sub.5 H H CH.sub.2 OCOCH.sub.3      CHO     ##STR131##      H H CH.sub.2 SCOCH.sub.3  C(CH.sub.3).sub.3 CH.sub.3 H H CH.sub.2     OCOCH.sub.3      C(CH.sub.3).sub.3 CH.sub.3 H H     ##STR132##       CH.sub.3 CH.sub.3 H H CH.sub.2 OCOCH.sub.3 COOC(CH.sub.3).sub.3     CH.sub.3 H OCH.sub.3 CH.sub.2 OCOCH.sub.3      ##STR133##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      ##STR134##      C.sub.2 H.sub.5 H H CH.sub.2 OCOCH.sub.3      ##STR135##      CH.sub.3 H H CH.sub.2 OCOCH.sub.3      H H H H     ##STR136##      ##STR137##      H H H      ##STR138##      H H     ##STR139##      H      ##STR140##      H CH.sub.3 H H     ##STR141##      H H H H     ##STR142##      H H H OCH.sub.3     ##STR143##      H CH.sub.3 H H     ##STR144##      ##STR145##      CH.sub.3 H H      ##STR146##       H CH.sub.3 CH.sub.2      OCC(CH.sub.3).sub.3 H     ##STR147##      H CH.sub.3     ##STR148##      H      ##STR149##      H CH.sub.3     ##STR150##      H      ##STR151##      H CH.sub.2CHCH.sub.2 CH.sub.2CCl.sub.3 H     ##STR152##      H     ##STR153##      H H      ##STR154##      ##STR155##      CH.sub.3 H H      ##STR156##      ##STR157##      CH.sub.3 H H      ##STR158##       H CH.sub.2 CO.sub.2      H H H     ##STR159##       H CH.sub.2      CONH.sub.2 H H     ##STR160##       H CH.sub.2      CONHCH.sub.3 H H     ##STR161##      H     ##STR162##      H H      ##STR163##      H C(CH.sub. 3).sub.3     ##STR164##      H      ##STR165##      H     ##STR166##      H H      ##STR167##      H CH.sub.3 C(CH.sub.3).sub.3 H     ##STR168##      H     ##STR169##      H H      ##STR170##      H     ##STR171##      H H      ##STR172##      H CH.sub.3 H OCH.sub.3     ##STR173##       H C.sub.2      H.sub.5 H H     ##STR174##       H C.sub.3 H.sub.7      n H H     ##STR175##      H CH.sub.2CHCH.sub.2 H H     ##STR176##      H CH.sub.2CHCHCH.sub.3 H H     ##STR177##       H C.sub.4 H.sub.9      n H H     ##STR178##      H     ##STR179##      H H      ##STR180##      H     ##STR181##      H H      ##STR182##      H     ##STR183##      H H      ##STR184##       H CH.sub.2      COOCH.sub.3 H H     ##STR185##       H CH.sub.2 COOC.sub.2      H.sub.5 H H     ##STR186##      H     ##STR187##      H H      ##STR188##      H     ##STR189##      H H      ##STR190##      H     ##STR191##      H H      ##STR192##      H     ##STR193##      H H      ##STR194##      H     ##STR195##      H H      ##STR196##      H     ##STR197##      H H      ##STR198##      H     ##STR199##      H H      ##STR200##      H     ##STR201##      H H      ##STR202##      H     ##STR203##      H H      ##STR204##      H     ##STR205##      H H      ##STR206##      H     ##STR207##      H H      ##STR208##       H CH.sub.2 SO.sub.3      H H H     ##STR209##       H CH.sub.2 SO.sub.2      NH.sub.2     ##STR210##      H      ##STR211##       H H CH.sub.2      CCl.sub.3 H     ##STR212##       H CH.sub.3 CH.sub.2      CCl.sub.3 H     ##STR213##      H CH.sub.3     ##STR214##      H      ##STR215##      H H     ##STR216##      H      ##STR217##      H H     ##STR218##      H      ##STR219##      H H     ##STR220##      H      ##STR221##      H H     ##STR222##      H      ##STR223##      H H C(CH.sub.3).sub.3 H     ##STR224##      ##STR225##      CH.sub.3 H H      ##STR226##      ##STR227##      CH.sub.3 C(CH.sub.3).sub.3 H      ##STR228##      ##STR229##      CH.sub.3      ##STR230##      H      ##STR231##      ##STR232##      CH.sub.3      ##STR233##      H      ##STR234##      ##STR235##      ##STR236##      H OCH.sub.3      ##STR237##      ##STR238##      ##STR239##      H H      ##STR240##      ##STR241##      ##STR242##      ##STR243##      H      ##STR244##      H     ##STR245##      ##STR246##      H      ##STR247##      H CH.sub.3 H H     ##STR248##      ##STR249##      ##STR250##      H H      ##STR251##      H CH.sub.3 H H     ##STR252##      H H CH.sub.3 H     ##STR253##      H     ##STR254##       H H      ##STR255##      H     ##STR256##      H H      ##STR257##      H H H H     ##STR258##      H CH.sub.3 H H     ##STR259##      ##STR260##      CH.sub.3 H H      ##STR261##      H CH.sub.3 H H     ##STR262##      H CH.sub.3 H H     ##STR263##      H CH.sub.3 H H     ##STR264##      H H H H     ##STR265##      H H H H     ##STR266##      H CH.sub.3 H H     ##STR267##      H CH.sub.3     ##STR268##      H      ##STR269##      ##STR270##      CH.sub.3      ##STR271##      H      ##STR272##      ##STR273##      ##STR274##      ##STR275##      OCH.sub.3      ##STR276##      ##STR277##      CH.sub.3 H H      ##STR278##      H     ##STR279##      H H      ##STR280##      H H H H     ##STR281##      H H H H     ##STR282##      H CH.sub.3 H H     ##STR283##      H CH.sub.3     ##STR284##      H      ##STR285##      H CH.sub.3     ##STR286##      H      ##STR287##      H CH.sub.3     ##STR288##      H      ##STR289##      ##STR290##      CH.sub.3 C(CH.sub.3).sub.3 H      ##STR291##      H CH.sub.3 H H     ##STR292##      H H H H     ##STR293##      H CH.sub.3 H H     ##STR294##      H CH.sub.2CHCH.sub.2 H H     ##STR295##      H     ##STR296##      H H      ##STR297##      H H H H     ##STR298##      H CH.sub.3 H OCH.sub.3     ##STR299##      H     ##STR300##      H H      ##STR301##      H     ##STR302##      H H      ##STR303##      H     ##STR304##      CH.sub.3 H      ##STR305##      ##STR306##      CH.sub.3 H H      ##STR307##      ##STR308##      CH.sub.3 H H      ##STR309##      H H H H     ##STR310##      H CH.sub.3 H H     ##STR311##      H H H OCH.sub.3     ##STR312##      H CH.sub.3     ##STR313##      H      ##STR314##      H CH.sub.3     ##STR315##      H      ##STR316##      H CH.sub.3 H H     ##STR317##      H CH.sub.3 H H     ##STR318##      H H H H     ##STR319##      H H H H     ##STR320##      H CH.sub.3 C(CH.sub.3).sub.3 H     ##STR321##      H H H H     ##STR322##      H CH.sub.3 H H     ##STR323##      H CH.sub.3     ##STR324##      H      ##STR325##      H CH.sub.3     ##STR326##      H      ##STR327##      H CH.sub.3     ##STR328##      H      ##STR329##       H CH.sub.2      COOH H H     ##STR330##      H     ##STR331##      H H      ##STR332##       H CH.sub.2CO.sub.2      CH.sub.3 H H     ##STR333##      H     ##STR334##      H H      ##STR335##      ##STR336##      CH.sub.3 H H      ##STR337##      ##STR338##      CH.sub.3 H H      ##STR339##      ##STR340##      CH.sub.3 H H      ##STR341##      ##STR342##      CH.sub.3 H H      ##STR343##      ##STR344##      CH.sub.3 H H      ##STR345##      H     ##STR346##      H H      ##STR347##      H     ##STR348##      H H      ##STR349##      H CH.sub.3 H OCH.sub.3     ##STR350##      H     ##STR351##      H H      ##STR352##      H H     ##STR353##      H      ##STR354##      H H H H     ##STR355##      H CH.sub.3 H H     ##STR356##      ##STR357##      CH.sub.3 H H      ##STR358##      H H H H     ##STR359##      H CH.sub.3 H H     ##STR360##      H CH.sub.3 H H     ##STR361##      H H H H     ##STR362##      H CH.sub.3 H H     ##STR363##      H H H H     ##STR364##      H CH.sub.3 H H     ##STR365##       H CH.sub.2      COOH H H     ##STR366##      H     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H     ##STR846##      H CH.sub.3 H H     ##STR847##      H CH.sub.3 H H     ##STR848##       H CH.sub.2 CO.sub.2      H H H     ##STR849##      H CH.sub.3     ##STR850##      H      ##STR851##       H CH.sub.2      CONH.sub.2 H H     ##STR852##       H CH.sub.2      CONH.sub.2     ##STR853##      H      ##STR854##       C(C.sub.6      H.sub.5).sub.3 CH.sub.3 H H     ##STR855##      H H H H     ##STR856##      H CH.sub.3 H H     ##STR857##       H C.sub.2      H.sub.5 H H     ##STR858##      H CH.sub.3 H H     ##STR859##      H CH.sub.3     ##STR860##      H      ##STR861##      H CH.sub.3 H H     ##STR862##       BrCH.sub.2      CO CH.sub.3 H H     ##STR863##      H CH.sub.3 H H     ##STR864##       C.sub.6 H.sub.5 OCH.sub.2      CO CH.sub.3 H H     ##STR865##      H H H H     ##STR866##      H CH.sub.3 H H     ##STR867##      H CH.sub.3 H H     ##STR868##      H CH.sub.3 H H     ##STR869##      H CH.sub.3 H H     ##STR870##       H CH.sub.2      CONH.sub.2 H H     ##STR871##       H CH.sub. 2      CONH.sub.2     ##STR872##      H      ##STR873##      H CH.sub.3 H H     ##STR874##      H CH.sub.3 H H     ##STR875##       H C.sub.2      H.sub.5 H H     ##STR876##      H CH.sub.3 H H     ##STR877##      H COCH.sub.3 H H     ##STR878##       H COCH.sub.2      Cl H H     ##STR879##      H COCH.sub.3 H H     ##STR880##      H COCH.sub.3 H H     ##STR881##       H COCH.sub.2      Cl H H     ##STR882##      H CH.sub.3 H H     ##STR883##      H CH(CH.sub.3).sub.2 H H     ##STR884##       H C.sub.2      H.sub.5 H H     ##STR885##       BrCH.sub.2 CO C.sub.2      H.sub.5 H H     ##STR886##       H CH.sub.2 CO.sub.2      H H H     ##STR887##      H CH.sub.3 H H     ##STR888##      H CH.sub.3     ##STR889##      H      ##STR890##      H CH.sub.3 H H     ##STR891##      H CH.sub.2CHCH.sub.2 H H     ##STR892##      H CH.sub.3 H H     ##STR893##      H CH.sub.3 H H     ##STR894##      H CH.sub.3 H H     ##STR895##      H CH.sub.3 H H     ##STR896##      H CH.sub.3 H H     ##STR897##      H CH.sub.3 H H     ##STR898##      H CH.sub.3 H H     ##STR899##      H CH.sub.3 H H     ##STR900##      H CH.sub.3 H H     ##STR901##      H CH.sub.3 H H     ##STR902##      H CH.sub.3 H H     ##STR903##      H CH.sub.3 H H     ##STR904##      H CH.sub.3 H H     ##STR905##      H CH.sub.3 H H     ##STR906##      H CH.sub.3 H H     ##STR907##      H CH.sub.3 H H     ##STR908##       H CH.sub.2 CO.sub.2      H H H     ##STR909##      H     ##STR910##      H H      ##STR911##      H H H H     ##STR912##      H CH.sub.3 H H     ##STR913##      H     ##STR914##      H H      ##STR915##      H H H H     ##STR916##      H CH.sub.3     ##STR917##      H      ##STR918##       BrCH.sub.2      CO CH.sub.3 H H     ##STR919##      H CH.sub.3 H H     ##STR920##       H C.sub.2      H.sub.5     ##STR921##      H      ##STR922##       H C.sub.6      H.sub.5 H H     ##STR923##      H CH.sub.3 H H     ##STR924##       BrCH.sub.2      CO CH.sub.3 H H     ##STR925##       (C.sub.6 H.sub.5).sub.3      C CH.sub.3 H H     ##STR926##      H H H H     ##STR927##      H CH.sub.3 H H     ##STR928##      H CH.sub.3 H H     ##STR929##      H CH.sub.3     ##STR930##      H      ##STR931##      H H H H     ##STR932##      H CH.sub.3 H H     ##STR933##       H CH.sub.2 CO.sub.2      H H H     ##STR934##      H CH.sub.3 H     ##STR935##       H CH.sub.2      CONHCH.sub.3 H     ##STR936##      H CH.sub.3 H H     ##STR937##      H CH.sub.3 H H     ##STR938##      H CH.sub.3 H H     ##STR939##      H CH.sub.3 H H     ##STR940##      H CH.sub.3 H H     ##STR941##      H CH.sub.3 H H     ##STR942##      H CH.sub.3 H H     ##STR943##      H CH.sub.3 H H     ##STR944##      H CH.sub.3 H H     ##STR945##      H CH.sub.3 H H     ##STR946##      H CH.sub.3 H H     ##STR947##      H CH.sub.3 H H     ##STR948##      H CH.sub.2COOH H H     ##STR949##      H CH.sub.2CHCH.sub.2 H H     ##STR950##      H CH.sub.2CH.sub.3     ##STR951##      H      ##STR952##      H CH.sub.3 H H     ##STR953##      H CH.sub.3 H H     ##STR954##      ##STR955##      ##STR956##      H H      ##STR957##      H CH.sub.2CH.sub.2CH.sub.3 H H     ##STR958##      H CH.sub.3 H H     ##STR959##      H H H H     ##STR960##      H     ##STR961##      H H      ##STR962##      H CH.sub.2CH.sub.2 CH.sub.2CH.sub.3 H H     ##STR963##      H CH.sub.3     ##STR964##      H      ##STR965##      H CH.sub.3 H H     ##STR966##      ##STR967##      CH.sub.2CH.sub.3 H H      ##STR968##      H CH.sub.2CHCH.sub.2 H OCH.sub.3     ##STR969##      H H H H     ##STR970##      H CH.sub.3 CH.sub.2COOH H     ##STR971##      H     ##STR972##      H H      ##STR973##      H     ##STR974##      H OCH.sub.3      ##STR975##      H CH.sub.3     ##STR976##      H      ##STR977##      ##STR978##      ##STR979##      H H      ##STR980##      ##STR981##      ##STR982##      H H      ##STR983##      H CH.sub.3 H H     ##STR984##      H     ##STR985##      H H      ##STR986##      ##STR987##      CH.sub.2CHCH.sub.2 H H      ##STR988##      H     ##STR989##      ##STR990##      H      ##STR991##      H     ##STR992##      H H      ##STR993##      ##STR994##      CH.sub.2CH.sub.2CH.sub.2 Cl H OCH.sub.3      ##STR995##      H CH.sub.2CHCHCOOH H H     ##STR996##       H CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CO.sub.2 C.sub.2      H.sub.5 H     ##STR997##      ##STR998##      CH.sub.2CONH.sub.2 H H      ##STR999##      H     ##STR1000##      H H      ##STR1001##      H     ##STR1002##      H H      ##STR1003##      H     ##STR1004##      ##STR1005##      H      ##STR1006##      H     ##STR1007##      H H      ##STR1008##      H     ##STR1009##      H H      ##STR1010##      H CH.sub.2COOCH.sub.3 H H     ##STR1011##      H CH.sub.2CH.sub.3 H H     ##STR1012##      H CH.sub.3 H H     ##STR1013##      H     ##STR1014##      H H      ##STR1015##      H CH.sub.2CH.sub.3     ##STR1016##      H      ##STR1017##      ##STR1018##      CH.sub.3 H H      ##STR1019##      H     ##STR1020##      H OCH.sub.3      ##STR1021##      H H     ##STR1022##      H      ##STR1023##       H CH.sub.2CHCHCH.sub.3 H H     ##STR1024##      ##STR1025##      ##STR1026##      H H      ##STR1027##      H H H H     ##STR1028##      ##STR1029##      CH.sub.2CHCHCH.sub.3 H H      ##STR1030##      H     ##STR1031##      H H      ##STR1032##      H CH.sub.3     ##STR1033##      H      ##STR1034##      H H H OCH.sub.3     ##STR1035##      ##STR1036##      ##STR1037##      H H      ##STR1038##      H CH.sub.2CCH H H     ##STR1039##       H CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2CO.sub.2 C.sub.2 H.sub.5 H      ##STR1040##      ##STR1041##      CH.sub.2CH.sub.2CH.sub.3 H H      ##STR1042##      H     ##STR1043##      H H      ##STR1044##      ##STR1045##      ##STR1046##      H H      ##STR1047##      H     ##STR1048##      H H      ##STR1049##      H     ##STR1050##      ##STR1051##      H      ##STR1052##      H H H H     ##STR1053##      H CH.sub.3 H OCH.sub.3     ##STR1054##      H CH.sub.2CH.sub.2CH.sub.3     ##STR1055##      H      ##STR1056##      ##STR1057##      CH.sub.2CH.sub.3 H H      ##STR1058##      H     ##STR1059##      H H      ##STR1060##       H CH.sub.2SO.sub.3      H H H     ##STR1061##      H CH.sub.2CH.sub.2OH H OCH.sub.3     ##STR1062##      ##STR1063##      CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H H      ##STR1064##      H H H H     ##STR1065##      H CH.sub.3 H H     ##STR1066##      H     ##STR1067##      H H      ##STR1068##      H CH.sub.2CH.sub.3     ##STR1069##      H      ##STR1070##      H     ##STR1071##      H H      ##STR1072##      H CH.sub.3 H H     ##STR1073##       H CH.sub.2      CH.sub.3 H H     ##STR1074##      H H H H     ##STR1075##      ##STR1076##      CH.sub.3 H H      ##STR1077##      H CH.sub.3 H H     ##STR1078##      H CH.sub.2CH.sub.3     ##STR1079##      H      ##STR1080##      ##STR1081##      CH.sub.2CH.sub.2CH.sub.3 H H      ##STR1082##      H     ##STR1083##      H H      ##STR1084##      H CH.sub.2CH.sub.3 H OCH.sub.3     ##STR1085##      H     ##STR1086##      H H      ##STR1087##      H CH.sub.2CHCH.sub.2     ##STR1088##      H      ##STR1089##      H H H     ##STR1090##       H C.sub.2      H.sub.5 H OCH.sub.3     ##STR1091##      H CH.sub.2CCH     ##STR1092##      H      ##STR1093##      ##STR1094##      ##STR1095##      H H      ##STR1096##      H     ##STR1097##       H H      ##STR1098##      H CH.sub.3 H H     ##STR1099##      ##STR1100##      CH.sub.2SO.sub.2      NH.sub.2 H H     ##STR1101##      H CH.sub.2CH.sub.2SCH.sub.3     ##STR1102##      H      ##STR1103##      H     ##STR1104##      Si(CH.sub.3).sub.3 H      ##STR1105##      H CH.sub.3     ##STR1106##      H      ##STR1107##      ##STR1108##      CH.sub.2COOH H H      ##STR1109##      H     ##STR1110##      H H      ##STR1111##      H     ##STR1112##      H OCH.sub.3      ##STR1113##      H CH.sub.2CHCHCH.sub.3     ##STR1114##      H      ##STR1115##      H H H H     ##STR1116##       H CH.sub.2CH.sub.2SO.sub.3 C.sub.2      H.sub.5 H H     ##STR1117##      H CH.sub.2CH.sub.2OH H OCH.sub.3     ##STR1118##      ##STR1119##      CH.sub.3      ##STR1120##      H      ##STR1121##      ##STR1122##      CH.sub.2CO.sub.2      CH.sub.3 H H     ##STR1123##      H H H H     ##STR1124##      H     ##STR1125##      H OCH.sub.3      ##STR1126##      H     ##STR1127##      H H      ##STR1128##      H CH.sub.3     ##STR1129##      H      ##STR1130##      ##STR1131##      ##STR1132##      H H      ##STR1133##      ##STR1134##      CH.sub.2CH.sub.2CH.sub.2CH.sub.3 H H      ##STR1135##      H     ##STR1136##      ##STR1137##      H      ##STR1138##      H H H H     ##STR1139##      ##STR1140##      CH.sub.3 H H      ##STR1141##      H     ##STR1142##      ##STR1143##      H      ##STR1144##       H CH.sub.2CO.sub.2      C(CH.sub.3).sub.3     ##STR1145##      OCH.sub.3      ##STR1146##      ##STR1147##      ##STR1148##      H H      ##STR1149##      H     ##STR1150##      C.sub.12      H.sub.25 H     ##STR1151##      ##STR1152##      CH.sub.3 H H      ##STR1153##      ##STR1154##      CH.sub.2CH.sub.2 OCH.sub.3 H H      ##STR1155##      H H H H     ##STR1156##      H CH.sub.2CH.sub.3 H OCH.sub.3     ##STR1157##      H     ##STR1158##      CH.sub.2CN H      ##STR1159##      H CH.sub.2CHCH.sub.2     ##STR1160##      H      ##STR1161##      ##STR1162##      ##STR1163##      H H      ##STR1164##      ##STR1165##      ##STR1166##      H H      ##STR1167##      H     ##STR1168##      H H      ##STR1169##      ##STR1170##      CH.sub.2CH.sub.2SCH.sub.3 H H      ##STR1171##       H CH.sub.2CO.sub.2 CH.sub.3 CH.sub.2CO.sub.2      CH.sub.3 H     ##STR1172##      ##STR1173##      CH.sub.3      ##STR1174##      OCH.sub.3      ##STR1175##      H H     ##STR1176##      H      ##STR1177##      H     ##STR1178##      H H      ##STR1179##      H H H H     ##STR1180##      H     ##STR1181##      H OCH.sub.3      ##STR1182##      ##STR1183##      ##STR1184##      H H      ##STR1185##      H SO.sub.2CH.sub.3 H H     ##STR1186##      H CH.sub.2CO.sub.2C(CH.sub.3).sub.3     ##STR1187##      H      ##STR1188##      H CH.sub.3     ##STR1189##      H      ##STR1190##      H     ##STR1191##      ##STR1192##      OCH.sub.3      ##STR1193##      ##STR1194##      ##STR1195##      H H      ##STR1196##      H H H H     ##STR1197##      ##STR1198##      CH.sub.2CH.sub.2CH.sub.3 CH.sub.2COOH H      ##STR1199##      ##STR1200##      ##STR1201##      H H      ##STR1202##      H     ##STR1203##      H H      ##STR1204##      ##STR1205##      CH.sub.2CHCH.sub.2 H H      ##STR1206##      H     ##STR1207##      H H      ##STR1208##       H C.sub.2      H.sub.5 H H     ##STR1209##      H     ##STR1210##      ##STR1211##      H      ##STR1212##      ##STR1213##      ##STR1214##      H H      ##STR1215##      H     ##STR1216##      H OCH.sub.3      ##STR1217##      H H H H     ##STR1218##      H CH.sub.2CHCH.sub.2     ##STR1219##      H      ##STR1220##      ##STR1221##      ##STR1222##      H H      ##STR1223##      H CH.sub.2CHCHCH.sub.3 H H     ##STR1224##      H     ##STR1225##      ##STR1226##      H      ##STR1227##      ##STR1228##      CH.sub.3      ##STR1229##      H      ##STR1230##      H CH.sub.2CH.sub.2 CH.sub.3 H H     ##STR1231##       H CH.sub.2CO.sub.2      C(CH.sub.3).sub.3     ##STR1232##      H      ##STR1233##      ##STR1234##      CH.sub.3 H H      ##STR1235##      H H H H     ##STR1236##      H     ##STR1237##      H H      ##STR1238##      H     ##STR1239##      ##STR1240##      H      ##STR1241##      ##STR1242##      ##STR1243##      H H      ##STR1244##      H H H H     ##STR1245##       H CH.sub.2CO.sub.2      CH.sub.3 H OCH.sub.3     ##STR1246##      H CH.sub.2CHCH.sub.2     ##STR1247##      H      ##STR1248##      ##STR1249##      C.sub.2 H.sub.5 CH.sub.2CO.sub.2 C.sub.2      H.sub.5 H     ##STR1250##      ##STR1251##      ##STR1252##      H H      ##STR1253##      H CH.sub.3     ##STR1254##      H      ##STR1255##      H     ##STR1256##      ##STR1257##      H      ##STR1258##      ##STR1259##      CH.sub.2CONH.sub.2 H H      ##STR1260##       H CH.sub.2CHCHCO.sub.2      H     ##STR1261##      H      ##STR1262##      H  CH.sub.3 H H     ##STR1263##      ##STR1264##      CH.sub.2CH.sub.2SCH.sub.3 H H      ##STR1265##      ##STR1266##      ##STR1267##      H H      ##STR1268##      H     ##STR1269##      ##STR1270##      H      ##STR1271##      H CH.sub.2CHCH.sub.2     ##STR1272##      H      ##STR1273##      H CH.sub.3     ##STR1274##      H      ##STR1275##      ##STR1276##      ##STR1277##      H H      ##STR1278##      ##STR1279##      ##STR1280##      H H      ##STR1281##       H CH.sub.2CHCH.sub.2 CH.sub.2CO.sub.2 C.sub.2      H.sub.5 H     ##STR1282##      H     ##STR1283##      ##STR1284##      H      ##STR1285##

The above table also relates to compounds of the general formula XIIwhich contain a --SO₂ group instead of the --SO group.

The compounds of the general formula I in which R₁ represents hydrogen,R₂ represents hydrogen, alkyl with 1-4 C atoms, preferably methyl,ethyl, propyl or butyl, alkenyl with 3-4 C atoms, such as, for example,allyl, or alkyl with 1-4 C atoms which is substituted by carboxyl oralkoxycarbonyl with 1-4 C atoms in the alkoxy radical, in particularcarboxymethyl, methoxycarbonylmethyl and ethoxycarbonylmethyl, R₃represents hydrogen, a cation, preferably an alkali metal, in particularsodium, or an ester group, preferably acyloxymethyl, carboxyalkyl orphthalide, R₄ represents hydrogen, X represents SO and A representsacetoxymethyl or the group --SR₅, R₅ having the preferred meaningsindicated above, are particularly interesting according to theinvention.

The following embodiment examples of syn-compounds which can bemanufactured according to the invention serve to further illustrate theinvention but do not limit it thereto.

EXAMPLE 1 The 1-S-oxide of7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid

7 g (0.01 mole) of7-[2-(2-tritylaminothiazol-4yl)-2-methoxyimino-acetamino]-cephalosporanicacid are dissolved in 25 ccs of tetrahydrofuran. A solution of 2.1 g(0.012 mole) of 3-chloroperoxybenzoic acid in 6 ccs of tetrahydrofuranis added dropwise at 10° C., while stirring, and the solution is furtherstirred for one hour and poured into 750 ccs of ether. 5.1 g of thetitle compound precipitate and are washed with ether and are dried invacuo over phosphorus pentoxide. Decomposition point: from 160° C.

R_(f) value: 0.51 (Merck thin layer chromatography silica gel, ethylacetate/i-propanol/water 4:3:2).

NMR (ppm, 60 MHz, (CD₃)₂ SO): 2.05 (3H, s, CH₃ --CO), 3.88 (3H, s,--OCH₃), 6.85 (1H, s, aromatic H) and 7.4 (15 H, trityl-H).

Neutral salts of the alkali metal series and alkaline earth metal seriesand salts with aromatic bases are obtained by bringing togetherequivalent amounts of one of these bases and the title compound in waterand freeze-drying the filtered solution.

A crystalline sodium salt was obtained as follows: 1.2 g of freeze-driedsodium salt is dissolved in 50 ccs of methanol, the solution is filteredwith charcoal and ether is added to the filtrate until the solutionstarts to become turbid. On trituration, 0.8 g of the sodium salt of the1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid crystallizes out as the dihydrate:

C₁₆ H₁₆ N₅ NaO₈ S₂.2H₂ O (529.4). Calculated: C, 36.3; H, 3.8; N, 13.2;S, 12.1. Found: C, 36.2; H, 3.8; N, 13.4; S, 12.0.

EXAMPLE 2 The 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid

(a) 5 g (0.007 mole) of the 1-S-oxide of7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid (Example 1) are introduced into 30 ccs of 50% strength aqueousformic acid at 50° C., while stirring, the mixture is further stirredfor 20 minutes and cooled to room temperature and the triphenylcarbinolis filtered off and rinsed with about 100 ccs of water. On cooling thefiltrate, 1.3 g of the title compound crystallize out.

(b) 12.8 g (0.028 mole) of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid are dissolved in 85 ccs of formic acid, and 28 ccs of methanol areadded. A solution of 5.0 g (0.029 mole) of 3-chloroperoxybenzoic acid in28 ccs of tetrahydrofuran is added dropwise at room temperature, whilestirring, the reaction mixture is further stirred for 50 minutes andpoured into 1 l of ether and the precipitate is filtered off. Forfurther purification, the precipitate is dissolved in 45 ccs of formicacid, a mixture of 1 l of methanol and 330 ccs of water is added and,after cooling with ice for half an hour, the crystalline product isfiltered off, washed with methanol and dried.

10.5 g of the title compound are obtained.

(c) 5.2 g (0.01 mole) of the formate of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporinicacid (monohydrate) are dissolved in a mixture of 50 ccs oftetrahydrofuran and 10 ccs of water. A solution of 2.5 g of 82% strength3-chloro-peroxybenzoic acid (corresponding to 0.012 mole) in 6 ccs oftetrahydrofuran is added dropwise at 10° C., whilst stirring. Some ofthe reaction product already crystallizes out during the dropwiseaddition. After stirring for one hour, the precipitate is filtered off,washed with tetrahydrofuran and dried in vacuo. 3.2 g of the 1-S-oxideof 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid are obtained. The compound slowly becomes discolored from 170° anddecomposes completely above 300°. It can optionally be recrystallizedfrom a mixture of formic acid/methanol/H₂ O.

C₁₆ H₁₇ N₅ O₈ S₂ ×H₂ O (489.5). Calculated: C, 39.2; H, 3.9; N, 14.3; S,13.1. Found: C, 39.4; H, 3.9; N, 14.2; S, 13.3.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 2.05 (3H, S, CH₃ CO), 3.77 (2H, q,2--CH₂), 3.88 (3H, S, O--CH₃), 4.90 (2H, q, 3--C--CH₂ O), 4.97 (1H, d,6--H), 5.92 (1H, q, 7--H), 6.85 (1H, S, aromatic H), 7.17 (2H, S, --NH₂)and 8.85 (1H, d, CONH--).

R_(f) value: 0.34 (Merck thin layer chromatography silica gel/ethylacetate/i-propanol/water 4:3:2), R_(f) of the starting compound: 0.46.

EXAMPLE 3 The 1-S-oxide of7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamino]-cephalosporanic acid

Stage 1: 7.1 g (0.01 mole) of7-[2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid are dissolved in 16 ccs of tetrahydrofuran, and a solution of 1.7 g(0.01 mole) of 3-chloroperoxybenzoic acid in 5 ccs of tetrahydrofuran isadded dropwise at 20° C., while stirring. After stirring for one hour,the reaction mixture is poured into 300 ccs of ether. 7.2 g of the1-S-oxide of7-[2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid precipitate and are washed with ether and dried in air. Thiscompound can be used for stage 2 without further purification.

Stage 2: 7.2 g of the 1-S-oxide of7-[2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid are dissolved in 32 ccs of 80% strength aqueous formic acid, thesolution is stirred at room temperature for two hours, 25 ccs of waterare added, the triphenylcarbinol is filtered off and the filtrate isconcentrated in vacuo. On trituration with ethanol and standing in arefrigerator, the amorphous residue becomes crystalline. After filteringoff and drying in vacuo, 2.7 g of the 1-S-oxide of7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamino]-cephalosporanicacid, which slowly decomposes above 250° C., are obtained.

C₁₇ H₁₉ N₅ O₈ S₂ ×1H₂ O (503.5) Calculated: C, 40.6; H, 4.2; N, 13.9; S,12.7, Found: C, 40.7; H, 4.1; N, 13.7; S, 13.2.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 1.27 (3H, t, C--CH₃), 2.07 (3H, S, COCH₃),3.77 (2H, q, 2--CH₂), 4.13 (2H, q, O--CH₂ --), 4.90 (2H, q, 3--C--CH₂--O), 4.97 (1H, d, 6--H), 5.92 (1H, q, 7--H), 6.80 (1H, S, aromatic H),7.17 (2H, S, --NH₂) and 8.67 (1H, d, CONH--).

EXAMPLE 4 The 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-propoxyimino-acetamino]-cephalosporanicacid

Stage 1: 68 g (0.43 mole) of ethyl 2-hydroxyimino-acetoacetate aredissolved in 350 ccs of acetone, 70.7 g of anhydrous potassium carbonateand 58.9 g (0.43 mole) of propyl mesylate are added and the mixture isboiled under reflux for 9 hours. The salts are filtered off and rinsedwith acetone, the solution is concentrated, the residue is taken up inmethylene chloride and the methylene chloride solution is washed withsodium carbonate solution and water. Drying and concentrating themethylene chloride solution leaves 70 g of ethyl2-propoximino-acetoacetate as an oil.

Stage 2: One tenth of a solution of 17.8 ccs (0.35 mole) of bromine in70 ccs of methylene chloride is added to 70 g (0.35 mole) of ethyl2-propoxyimino-acetoacetate in 350 ccs of methylene chloride at 25° C.,while stirring and irradiating with UV light. After the bromine layerhas disappeared, the rest of the bromine solution is slowly addeddropwise. The mixture is further stirred for 30 minutes and poured ontoice and the organic phase is separated, washed until neutral andconcentrated.

85 g of ethyl 4-bromo-2-propoxyimino-acetoacetate are obtained as anoil.

Stage 3: 85 g of ethyl 4-bromo-2-propoxyimino-acetoacetate are addeddropwise to 23 g (0.3 mole) of thiourea in 155 ccs of water and 75 ccsof ethanol at 25°, while stirring. After one hour, the hydrobromidewhich has precipitated in the meantime is decomposed by addingconcentrated ammonia up to pH 6. After filtering off the product,washing with water and diisopropyl ether and drying, 45 g of ethyl2-(2-aminothiazol-4-yl)-2-propoxyimino-acetate are obtained.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 0.77-1.8 (8H, m, 2×CH₃, --CH₂ --), 3.9-4.5(4H, 2×--O--CH₂), 6.97 (1H, S, aromatic H) and 7.27 (2H, S, NH₂).

Stage 4: 30 ccs of triethylamine are added to 45 g (0.18 mole) of ethyl2-(2-aminothiazol-4-yl)-2-propoxyimino-acetate in 120 ccs ofdimethylformamide and 175 ccs of methylene chloride, and 59 g (0.21mole) of trityl chloride (97% pure) are introduced in portions. Afterstirring the mixture for four hours, 175 ccs of methylene chloride areadded and the organic phase is washed with water until free fromchlorine ions. The dried solution gives, after concentrating, 90 g ofethyl 2-propoximino-2-(2-tritylaminothiazol-4-yl)-acetate, which isemployed for the next stage without purification.

Stage 5: 90 g (0.18 mole) of ethyl2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetate are dissolved in420 ccs of dioxan, 105 ccs (0.21 mole) of 2N sodium hydroxide solutionare added dropwise at 85°, while stirring, and the mixture is kept atthis temperature for one hour. On cooling, the sodium salt of2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid crystallineout. It is filtered off, washed with a mixture of dioxan/ether 1:1 andthen with acetone and dried at 80° C. The acid is liberated bysuspending the sodium salt in chloroform, adding the equivalent amountof 1N hydrochloric acid, shaking the mixture and washing the chloroformsolution with water. After stripping off the solvent, 46 g of2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid, which stillcontains some chloroform but is employed directly for the coupling with7-aminocephalosporanic acid, are obtained.

Stage 6: 46 g (0.088 mole) of2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid (90% pure) in120 ccs of chloroform are added dropwise to a solution, cooled to +5°,of 10.7 g of dicyclohexylcarbodiimide in 70 ccs of chloroform, whilestirring. After stirring for two hours, the dicyclohexylurea which hasprecipitated is separated. A solution of 11.9 g of7-aminocephalosporanic acid and 150 ccs of triethylamine in 180 ccs ofmethylene chloride is added dropwise to the filtrate, which has beencooled to -10° C., while stirring. After stirring the mixture is at roomtemperature for three hours, it is carefully acidified with 110 ccs of 1N hydrochloric acid, unreacted 7-aminocephalosporanic acid is filteredoff and the filtrate is washed with water until neutral, dried andconcentrated. The residue (about 60 g) is dissolved in 110 ccs ofdioxan, the solution is filtered with a little charcoal, and 110 ccs ofether and 13.5 ccs of diethylamine are added to the filtrate. On coolingin ice, 19 g of the diethylamine salt of2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid areprecipitated as crystals. After stripping off the solvent, 42 g ofresidue remain which, when triturated with ether, give 27 g of the crudediethylamine salt of the coupling product. A solution of this salt in300 ccs of solution is shaken with the equivalent amount of 1Nhydrochloric acid, the reaction mixture is added with water untilneutral, dried and filtered with charcoal and the filtrate isconcentrated. When triturated with ether and dried, the residue gives 20g of7-[2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid.

Stage 7: 4.4 g (0.006 mole) of7-[2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid are dissolved in 25 ccs of 80% strength aqueous formic acid and thesolution is stirred at room temperature for 2 hours. On adding 25 ccs ofwater, triphenylcarbinol precipitates. The filtrate is concentrated andthe residue is triturated with ether and dried.

2.3 g of7-[2-(2-aminothiazol-4-yl)-2-propoxyimino-acetamino]-cephalosporanicacid, which slowly decomposes from 120°, are obtained.

Stage 8: 14.5 g (0.02 mole) of stage 6 are dissolved in 35 ccs oftetrahydrofuran and a solution of 4.85 g (0.022 mole) of3-chloroperoxybenzoic acid (78.3% pure) in 10 ccs of tetrahydrofuran isadded at 20° C. After stirring for one hour, the mixture is poured into1 l of ether and the precipitate is filtered off and dried. 11.6 g ofthe 1-S-oxide of7-[2-propoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid are obtained, the trityl group of which is split off analogously toExample 4, stage 7 using 80% strength formic acid. 6.3 g of the1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-propoxyimino-acetamino]-cephalosporanicacid are obtained:

C₁₈ H₂₁ N₅ O₈ S₂.1/2H₂ O (508.5). Calculated: C, 42.5; H, 4.4; N, 13.8;S, 12.6. Found: C, 42.5; H, 4.4; N, 13.5; S, 12.4.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 0.93 (3H, t, --CH₂ --CH₃), 1.66 (2H, m,--CH₂ --CH₂ --CH₃), 2.07 (3H, S, CH₃ CO), 3.9 (2H, q, 2--CH₂), 4.07 (2H,t, O--CH₂ --CH₂ --), 4.93 (2H, q, 3--C--CH₂ --O), 5.0 (1H, d, 6--H),5.93 (1H, q, 7--H), 6.80 (1H, s, aromatic H), 7.2 (2H, s, --NH₂) and8.67 (1H, d, CONH--).

EXAMPLE 5 The 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetamino]-cephalosporanicacid

Stage 1: Analogously to Example 4, stage 1, 79.5 g (0.5 mole) of ethyl2-hydroxyimino-acetoacetate and 68.3 g (0.45 mole) of n-butyl mesylategive 76 g of ethyl 2-n-butoxyimino-acetoacetate as a colorless oil.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 0.9-1.8 (10H, m, --CH₂ --CH₃, --CH₂ --CH₂--CH₃), 2.4 (3H, s, CH₃ --CO) and 4.1-4.6 (4H, t+q, 2×--O--CH₂ --).

Stage 2: 76 g (0.35 mole) of ethyl 2-n-butoxyimino-acetoacetate and 18ccs (0.35 mole) of bromine react analogously to Example 4, stage 2, togive 93 g of ethyl 4-bromo-2-n-butoxyimino-acetoacetate.

Stage 3: 93 g (0.32 mole) of ethyl 4-bromo-2-n-butoxyimino-acetoacetateand 24 g (0.32 mole) of thiourea undergo a condensation reactionanalogously to Example 4, stage 3, to give 35.2 g of ethyl2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetate of melting point129.5°-131°.

Stages 4 and 5: 35.2 g (0.13 mole) of ethyl2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetate are tritylated with 44.6g (0.155 mole) of trityl chloride (97% pure) analogously to Example 4,stage 4, and the product is split, without further purification, asdescribed in Example 4, stage 5, to give 37 g of2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid.

Stage 6: 37 g of 2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-aceticacid are coupled with 7-aminocephalosporanic acid analogously to Example4, stage 6. The crude diethylamine salt of the coupling product wasdissolved in 500 ccs of water, the solution was filtered with charcoaland the filtrate was acidified with 1N hydrochloric acid and extractedwith chloroform. The extract was dried and concentrated and the residuewas treated with ether. 10.5 g of7-[2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid are obtained.

Stage 7: 3.7 g (0.005 mole) of7-[2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid (stage 6) were detritylated analogously to Example 4, stage 7, togive 1 g of crystalline7-[2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetamino]-cephalosporanicacid, decomposition point >250°.

Stage 8: The oxidation and subsequent detritylation of 6.8 g (0.0092mole) of7-[2-n-butoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid to give the 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetamino]-cephalosporanicacid was carried out analogously to Example 4, stage 8.

C₁₉ H₂₃ N₅ O₈ S₂.1/2H₂ O (522.5). Calculated: C, 43.7; H, 4.6; N, 13.4;S, 12.3. Found: C, 43.6; H, 4.5; N, 13.3; S, 12.4.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 0.7-1.8 (7H, m, --CH₂ --CH₂ --CH₃), 2.07(3H, s, CH₃ CO), 3.9 (2H, q, 2--CH₂), 4.1 (2H, t, --O--CH₂ --CH₂ --),4.90 (2H, q, 3--C--CH₂ --O--), 5.0 (1H, d, 6--H), 5.93 (1H, q, 7--H),6.80 (1H, s, aromatic H), 7.2 (2H, s, --NH₂) and 8.67 (1H, d, CONH--).

EXAMPLE 6 Tert.-butyl 7-(2-hydroxybenzylideneamino)-cephalosporanate

3.3 g (0.01 mole) of tert.-butyl 7-aminocephalosporanate are dissolvedin 10.4 ccs (0.1 mole) of salicylaldehyde at room temperature, thesolution is left to stand for one hour, 100 ccs of petroleum ether areadded and the condensation product is filtered of and rinsed withpetroleum ether. After recrystallization from methylenechloride/cyclohexane, 3.6 g of the title compound of melting point156°-167° are obtained. The excess salicylaldehyde can be recovered bydistilling the mother liquor.

C₂₁ H₂₄ N₂ O₆ S (432.5). Calculated: C, 58.3; H, 5.6; N, 6.5; S, 7.4.Found: C, 58.1; H, 5.6; N, 6.3; S, 7.6.

EXAMPLE 7 The 1-R-oxide of tert.-butyl7-(2-hydroxybenzylideneamino)cephalosporanate

A solution of 12.6 g (0.06 mole) of 3-chloroperoxybenzoic acid (82%pure) in 10 ccs of tetrahydrofuran is added dropwise to 21.6 g (0.05mole) of tert.-butyl 7-(2-hydroxybenzylideneamino)-cephalosporanate,dissolved in 100 ccs of tetrahydrofuran, at 10°, while stirring. Afterstirring at the same temperature for one hour, 500 ccs of water areadded and the mixture is adjusted to pH 8 with bicarbonate solution andstirred further until the initially oily precipitate has solidified. Theprecipitate is filtered off, rinsed successively with bicarbonate, waterand ether and dried.

17.8 of the title compound of decomposition point 153°-155° C. areobtained.

C₂₁ H₂₄ N₂ O₇ S (448.5) Calculated: C, 56.2; H, 5.4; N, 6.3; S, 7.2.Found: C, 56.3; H, 5.4; N, 6.2; S, 7.2.

R_(f) value: 0.4 (Merck 60 thin layer chromatography silica gel, ethylacetate).

Peroxyacetic acid, peroxybenzoic acid and monoperoxyphthalic acid, whichcan also be produced in situ, and hydrogen peroxide are similarlysuitable as oxidizing agents.

EXAMPLE 8 The 1-R-oxide of 7-aminocephalosporanic acid

12 g (0.035 mole) of the 1-R-oxide of tert.-butyl7-aminocephalosporanate (Example 9), dissolved in 120 ccs oftrifluoroacetic acid, are stirred at room temperature for one and a halfhours. The red-brown oil which remains after stripping off thetrifluoroacetic acid is dissolved in 200 ccs of water, the solution istreated twice with active charcoal, and solid sodium bicarbonate isadded to the yellowish filtrate until the pH value is 2.2. The titlecompound which has crystallized out is filtered off, washed with waterand dried in vacuo.

6.7 g of decomposition point 250° are obtained.

C₁₀ H₁₂ N₂ O₆ S (288.3). Calculated: C, 41.4; H, 4.2; N, 9.7; O, 33.3;S, 11.1. Found: C, 40.9; H, 4.2; N, 9.5; O, 33.1; S, 11.4.

NMR (ppm, 60 MHz, D₂ O+NaHCO₃): 2.13 (3H, s, CH₃ --O--), 4.0 (2H, q,3--C--CH₂ --O--), 4.86 (1H, d, 6--H) and 5.03 (1H, d, 7--H).

EXAMPLE 9 The 1-R-oxide of tert.-butyl 7-aminocephalosporanate

35.9 g (0.08 mole) of the 1R-oxide of tert.-butyl7-(2-hydroxybenzylideneamino)-cephalosporanate are suspended in 480 ccsof methanol, 17.6 g (0.1 mole) of Girard T reagent are introduced andthe mixture is warmed briefly to 35°-50° C. until a clear solutionforms. After stirring at room temperature for about half an hour, thesolution is concentrated and the residue is suspended and stirred in 500ccs of water. The title compound is filtered off and washed successivelywith water, isopropanol and ether.

23 g of decomposition point 170° are obtained.

C₁₄ H₂₀ N₂ O₆ S (344.4). Calculated: C, 48.8; H, 5.9; N, 8.1; S, 9.3.Found: C, 48.6; H, 6.0; N, 8.0; S, 9.3.

EXAMPLE 10 The 1-R-oxide of tert.-butyl7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanate

44.3 g (0.1 mole) of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-aceticacid in 150 ccs of methylene chloride are added dropwise to a solutionof 12.3 g (0.058 mole) of dicyclohexylcarbodiimide (97% pure) in 87 ccsof methylene chloride at 5°, while stirring, the mixture is stirred fora further 40 minutes and the temperature is allowed to rise to 20° inthe course of 30 minutes. Dicyclohexylurea which has precipitated isfiltered off, and a solution of 17.2 g (0.05 mole) of the 1-R-oxide oftert.-butyl 7-aminocephalosporanate in 150 ccs of methylene chloride isadded dropwise to the filtrate at -10°, while stirring. The mixture isfurther stirred at room temperature for 90 minutes and concentrated, theresidue is dissolved in 500 ccs of ethyl acetate, if appropriate alittle tetrahydrofuran being added, and 8 ccs (0.075 mole) ofdiethylamine are added. After cooling the mixture with ice for one hour,27 g of the diethylamine salt of the starting acid are filtered off andrinsed with ethyl acetate. After clarification with a little charcoal,the filtrate is shaken with 200 ccs of 0.5 N hydrochloric acid and theorganic phase is separated, washed with water until neutral, dried oversodium sulfate and concentrated until a thick crystal sludge forms. Thisis stirred with ether and the solid is filtered off, washed with etherand dried in vacuo. 25.2 g of the title compound of decomposition point175° are obtained.

C₃₉ H₃₉ N₅ O₈ S₂ (769.9). Calculated: C, 60.8; H, 5.1; N, 9.1; S, 8.3.Found: C, 60.5; H, 5.0; N, 9.0; S, 8.4.

R_(f) value: 0.48/thin layer chromatography, Merck 60 silica gel, ethylacetate.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 1.5 (9H, s, --C(CH₃)₃), 2.07 (3H, s, CH₃CO), 3.83 (3H, s, ═N--OCH₃), 3.93 (2H, q, 2--CH₂), 4.73 (2H, q,3--C--CH₂ --O), 4.97 (1H, d, 6--H), 5.73 (1H, q, 7--H), 6.87 (1H, s,aromatic H), 7.33 (15H, broad s, trityl), 8.8 (1H, s, NH) and 9.7 (1H,d, CONH--).

EXAMPLE 11 The 1-R-oxide of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamino]-cephalosporanic acid

3.1 g (0.004 mole) of the 1-R-oxide of tert.-butyl7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]cephalosporanateare introduced in portions into 30 ccs of trifluoroacetic acid at 0°,while stirring, the mixture is stirred for 2 hours, 60 ccs of water areadded and the triphenylcarbinol is filtered off. The filtrate isconcentrated in vacuo and the residue is triturated with ether. Thecrude title compound can be purified by column chromatography [MerckSiO₂ (particle size 0.06-0.2 mm), solvent: ethylacetate/isopropanol/water 4:3:2] and is converted into the sodium saltby dissolving in the equivalent amount of bicarbonate or sodiumhydroxide solution and freeze-drying. Decomposition point >300°. R_(f)value (free acid): 0.41 (thin layer chromatography, Merck 60 silica gel,ethyl acetate/isopropanol/water 4:3:2).

NMR (ppm, 60 MHz, (CD₃)₂ SO): 2.0 (3H, s, CH₃ CO), 3.37 (2H, q, 2--CH₂),3.87 (3H, s, O--CH₃), 4.80(H, d, 6--H), 4.83 (2H, q, 3--C--CH₂ --O),5.63 (H, q, 7--H), 6.93 (H, s, aromatic H), 7.17 (2H, s, NH₂) and 9.73(H, d, CONH--).

EXAMPLE 12 The 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylicacid

Stage 1: 7.2 g (0.015 mole) of the sodium salt of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid and 8.1 g (0.045 mole) of the sodium salt of5-mercapto-1-methyltetrazole dihydrate are dissolved in 175 ccs ofwater, the pH value of the solution is adjusted to 7 with sodiumbicarbonate solution and the solution is heated to 50° for 18 hours,under nitrogen. The reaction mixture is adjusted to pH 5 with 1N HCl andfiltered with charcoal and the filtrate is acidified to pH 2. Theprecipitate is filtered off, washed with water and dried over pentoxide.

3.4 g of7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamino]-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylicacid are obtained. A further preparation method for this compoundconsists in reacting7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid with 5-mercapto-1-methyl-tetrazole at pH 7±1 under analogousconditions and then splitting off the trityl protective group of thereaction product in 80% strength formic acid analogously to Example 3,stage 2, or with trifluoroacetic acid (0.5 to 1 hour at 0°-10°).

Stage 2: 1.9 g (0.037 mole) of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylicacid are dissolved in a mixture of 40 ccs of tetrahydrofuran and 25 ccsof formic acid, and 0.7 g (0.004 mole) of 3-chloroperoxybenzoic acid in3 ccs of tetrahydrofuran is added dropwise at room temperature, whilestirring. After stirring for half an hour, the small amount ofby-product which has precipitated is filtered off and the reactionproduct is precipitated with ether.

1.4 g of the title compound of decomposition point >>250° are obtained.The title compound is also obtained by coupling the 1-S-oxide of7-amino-3-(1-methyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acidand 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid analogouslyto Example 4, stage 6, and then splitting off the trityl protectivegroup with 80% strength formic acid or trifluoroacetic acid in themanner described above.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 3.87 and 3.93 (6H, two s, --OCH₃ andN--CH₃), 4.35 (2H, q, 3--CH₂ --S--), 4.93 (1H, d, 6--H), 5.83 (1H, q,7--H), 6.80 (1H, s, aromatic H), 7.15 (1H, s, NH₂) and 8.80 (1H, d,CONH--).

EXAMPLE 13 The 1,1-dioxide of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamino]-cephalosporanic acid

Route 1: A solution of 3.5 g (0.02 mole) of 3-chloroperoxybenzoic acidin 10 ccs of tetrahydrofuran is added dropwise to 4.6 g (0.01 mole) of7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamino]-cephalosporanic acidin 30 ccs of formic acid and 10 ccs of methanol at 20°, while stirring.After 20 hours, the mixture is poured into 750 ccs of ether and theprecipitate is filtered off, washed with ether and dried. For furtherpurification, all the crude product is stirred with 100 ccs of water forabout 20 minutes, whereupon the dioxide dissolves. The undissolvedimpurities are filtered off and the filtrate is freeze-dried. 2.2 g ofthe title compound are obtained.

Route 2: A solution of 0.76 g (0.0044 mole) of 3-chloroperoxybenzoicacid in 3 ccs of tetrahydrofuran is added dropwise to 1.4 g (0.002 mole)of7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanicacid in 5 ccs of tetrahydrofuran at room temperature, while stirring,and, after standing for 1.5 hours, the mixture is poured into 200 ccs ofether. The precipitate is filtered off, washed with ether and dried overphosphorus pentoxide. This product (0.9 g) is dissolved in 10 ccs of 80%strength aqueous formic acid, the solution is stirred at roomtemperature for 2 hours, 5 ccs of water are added and thetriphenylcarbinol which has separated out is filtered off. The filtrateis diluted with 50 ccs of water and clarified with charcoal, the formicacid is removed by concentrating the mixture in vacuo, a further 50 ccsof water are added to the residue and the solid is filtered off andfreeze-dried.

0.5 g of the title compound is obtained.

Route 3: 4.4 g (0.01 mole) of2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid and 1.8 g(0.005 mole) of the 1,1-dioxide of tert.-butyl 7-aminocephalosporanateare subjected to a condensation reaction analogously to Example 10 togive the 1,1-dioxide of tert.-butyl7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamino]-cephalosporanate,and the trityl protective group and tert.-butyl protective group aresplit off with trifluoroacetic acid in the manner already described.R_(f) value: 0.46 (thin layer chromatography, Merck 60 silica gel, ethylacetate, isopropanol, water 4:3:2).

NMR (ppm, 60 MHz, (CD₃)₂ SO): 2.03 (3H, s, COCH₃), 3.83 (3H, s, --OCH₃),3.5-5.3 (4H, m, 2--CH₂, 3--CH₂ --O--), 5.43 (1H, d, 6--H), 6.03 (1H, q,7--H), 6.77 (1H, s, aromatic H), 7.13 (2H, broad s, NH₂) and 9.6 (H, d,CONH--).

EXAMPLE 14 The 1,1-dioxide of tert.-butyl 7-amino-cephalosporanate

Stage 1: A solution of 4.2 g (0.024 mole) of 3-chloroperoxybenzoic acidin 15 ccs of tetrahydrofuran is added dropwise to 4.32 g (0.01 mole) oftert.-butyl 7-(2-hydroxy-benzylideneamino)-cephalosporanate (Example 6)in 20 ccs of tetrahydrofuran at room temperature, while stirring, andthe mixture is further stirred for 3.5 hours and cooled with ice. Thecrystals which have separated out (0.35 g) are filtered off. Theyconsist of a mixture of the sulfoxide and sulfone of the starting ester.On adding 200 ccs of ether to the filtrate and cooling further, 0.86 gof the 1,1-dioxide of tert.-butyl7-(2-hydroxy-benzylideneamino)-cephalosporanate crystallizes out.

C₂₁ H₂₄ N₂ O₈ S (464.5). Calculated: C, 54.3; H, 5.2; N, 6.0; S, 6.9.Found: C, 54.4; H, 5.3; N, 5.9; S, 7.1. R_(f) value: 0.63 (thin layerchromatography, Merck 60 silica gel, ethyl acetate).

Stage 2: The splitting off of the hydroxybenzylidene protective group iscarried out analogously to Example 9.

EXAMPLE 15 The 1-S-oxide of ethoxy-ethoxycarbonyl-methyl7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanate

0.71 g (0.0043 mole) of ethyl 2-ethoxy-2-chloroacetate (boiling point₁₃82°-83° C.) is added dropwise to a solution of 2 g (0.0043 mole) of the1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid (Example 2) and 0.6 cc (0.0044 mole) of triethylamine in 20 ccs ofdimethylformamide at room temperature, while stirring, the mixture isfurther stirred for 30 minutes and the solvent is stripped off in vacuo.The residue is dissolved in chloroform and the solution is washed withwater and sodium bicarbonate and, after drying with sodium sulfate, isconcentrated to 20 ccs. It is poured into 250 ccs of ether, theprecipitate is filtered off and, after drying over phosphorus pentoxide,1.8 g of the title compound, which decomposes above 130° C., areobtained.

C₂₂ H₂₇ N₅ O₁₁ S₂ ×1/2 H₂ O (610.6). Calculated: C, 43.3; H, 4.6; N,11.5; S, 10.5. Found: C, 43.2; H, 4.6; N, 11.4; S, 10.5.

R_(f) value: 0.75 (Merck thin layer chromatography silica gel, ethylacetate/i-propanol/water 4:3:2).

EXAMPLE 16 The 1-S-oxide of methoxy-methoxycarbonyl-methyl7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanate

The title compound, decomposition point >150° C., was obtainedanalogously to Example 15 by reacting the 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid (Example 2) with methyl 2-chloro-2-methoxyacetate (boiling point₂₂75°-77° C.).

C₂₀ H₂₃ N₅ O₁₁ S₂ ×1/2 H₂ O (582.5). Calculated: C, 41.2; H, 4.2; N,12.0; S, 11.0. Found: C, 41.0; H, 4.2; N, 11.8; S, 11.2.

R_(f) value: 0.7 (Merck silica gel, ethyl acetate/i-propanol/water4:3:2).

EXAMPLE 17 The 1-S-oxide of propoxy-propoxycarbonyl-methyl7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanate

The title compound, which slowly decomposes from 140° C., was obtainedanalogously to Example 15 by reacting the 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid (Example 2) with propyl 2-chloro-2-propoxyacetate (boiling point₂₃115°-117° C.).

C₂₄ H₃₁ N₅ O₁₁ S₂ (629.6). Calculated: C, 45.8; H,5.0; N, 11.1; S, 10.2.Found: C, 45.5; H, 5.0; N, 11.0; S, 10.3.

EXAMPLE 18 The 1-S-oxide of n-butoxy-n-butoxycarbonyl-methyl7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanate

The title compound, which decomposes from 145° C., was obtainedanalogously to Example 15 by reacting the 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamino]-cephalosporanicacid (Example 2) with n-butyl 2-n-butoxy-2-n-butoxyacetate (boilingpoint₂₄ 145°-147° C.).

C₂₆ H₃₅ N₅ O₁₁ S₂ (657.7). Calculated: C, 47.5; H, 5.4; N, 10.7; S, 9.8.Found: C, 47.2; H, 5.4; N, 10.5; S, 9.8.

EXAMPLE 19 The 1-S-oxide of methoxy-methoxycarbonyl-methyl7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamino]-cephalosporanate

The title compound, which decomposes from 130° C., was obtainedanalogously to Example 15 by reacting the 1-S-oxide of7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamino]-cephalosporanic acid(Example 3) with methyl 2-chloro-2-methoxyacetate (boiling point₂₂75°-77° C.).

C₂₁ H₂₅ N₅ O₁₁ S₂ (587.8). Calculated: C, 42.9; H, 4.3; N, 11.9; S,10.9. Found: C, 42.5; H, 4.3; N, 11.7; S, 10.6.

EXAMPLE 20 The 1,1-dioxide of tert.-butyl7-(tert.-butoxycarbonylamino)cephalosporanate

Stage 1: 4.5 g (0.021 mole) of N-(tert.-butoxycarbonyloxy)succinimideare added to 6.6 g (0.02 mole) of tert.-butyl 7-aminocephalosporanate,dissolved in 25 ccs of pyridine. The mixture is stirred at roomtemperature for 7 hours, the pyridine is stripped off in vacuo and theresidue is triturated in water with the addition of 2 N HCl and filteredoff. 8.4 g of crude product are obtained which, after recrystallizationfrom methanol/H₂ O with the addition of active charcoal, gives 6.5 g oftert.-butyl 7-(tert.-butoxycarbonylamino)-cephalosporanate of meltingpoint 145°-146°.

Stage 2: A solution of 6.7 g (0.0304 mole) of 3-chloroperoxybenzoic acid(78.3% pure) in 10 ccs of tetrahydrofuran is added to 6.5 g (0.0152mole) of tert.-butyl 7-(tert.-butoxycarbonylamino)-cephalosporanate,dissolved in 30 ccs of tetrahydrofuran, at 20°, while cooling, and themixture is left to stand at room temperature for 16 hours. The oil whichhas been precipitated by adding 300 ml of water solidifies on treatmentwith sodium bicarbonate and, after recrystallization from acetone/water,gives 6 g of the title compound of decomposition point 178°-179°.

C₁₉ H₂₈ N₂ O₉ S (460.5). Calculated: C, 49.6; H, 6.1; N, 6.1; O, 31.3;S, 7.0. Found: C, 49.3; H, 5.8; N, 6.2; O, 31.3; S, 7.1.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 1.44 and 1.5 (18H, 2S, (CH₃)₃ CO--), 2.03(3H, S, CH₃ --CO--), 4.23 (2H, d, 2--CH₂), 4.78 (2H, q, 3--C--CH₂--O--), 5.32 (1H, d, 6H), 5.76 (1H, q, 7H) and 7.11 (1H, d, --CONH--).

EXAMPLE 21 The 1,1-dioxide of 7-aminocephalosporanic acid

2.3 g (0.005 mole) of the 1,1-dioxide of tert.-butyl7-(tert.-butoxycarbonylamino)-cephalosporanate (Example 20) aredissolved in 23 ccs of trifluoroacetic acid and the solution is left tostand at room temperature for 1.5 hours. The trifluoroacetic acid isstripped off in vacuo, 150 ml of water are added to the residue and thecrystals which are obtained are filtered off and dried in vacuo. 1.3 gof the title compound of decomposition point 179°-180° are obtained.

C₁₀ H₁₂ N₂ O₇ S (304.3). Calculated: C, 39.5; H, 4.0; N, 9.2; S, 10.5.Found: C, 39.7; H, 4.4; N, 8.9; S, 10.7.

NMR (ppm, 60 MHz, D₂ O+NaHCO₃): 2.12 (3H, s, CH₃ --CO--), 4.8 (2H, q,3--C--CH₂ --O--), 5.0 (1H, d, 6--H) and 5.16 (1H, d, 7--H).

EXAMPLE 22 The 1,1-dioxide of tert.-butyl 7-aminocephalosporanate

23 g (0.05 mole) of the 1,1-dioxide of tert.-butyl7-(tert.-butoxycarbonylamino)-cephalosporanate (Example 20) aredissolved in 115 ccs of trifluoroacetic acid at 25° and, after 5minutes, the reaction mixture is poured into 500 ccs of water. Thefiltered solution is adjusted to pH 8 with sodium bicarbonate. Afterfiltering off and drying the crystals, 10.6 g of the title compound ofdecomposition point 173° are obtained.

2.4 g of the 1,1-dioxide of 7-aminocephalosporanic acid (Example 21) areobtained by acidifying the mother liquor (pH 2).

C₁₄ H₂₀ N₂ O₇ S (360.4). Calculated: C, 46.7; H, 5.6; N, 7.8; O, 31.1;S, 8.9. Found: C, 46.4; H, 5.4; N, 7.5; O, 30.8; S, 9.2.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 1.48 (9H, s, (CH₃)₃ CO--), 2.02 (3H, s,CH₃ --CO--), 2.83 (2H, s, --NH₂), 4.15 (2H, q, 2--CH₂), 4.77 (2H, q,3--C--CH₂ --O--), 4.98 (1H, d, 6--H) and 5.18 (1H, d, 7--H).

EXAMPLE 23 The 1-S-oxide of 7-aminocephalosporanic acid

A solution of 4.6 g (0.021 mole) of 3-chloroperoxybenzoic acid (72.3%pure) is added dropwise to 5.5 g (0.02 mole) of 7-aminocephalosporanicacid, dissolved in 50 ccs of formic acid, at 20°. The mixture issubsequently stirred for 20 minutes, 40 ml of methanol are added, themixture is poured into 500 ml of ether and the precipitate is filteredoff and dried in vacuo. 4.9 g of the title compound of decompositionpoint 250° are obtained.

C₁₀ H₁₂ N₂ O₆ S (288.3). Calculated: C, 41.7; H, 4.2; N, 9.7; O, 33.3;S, 11.1. Found: C, 41.6; H, 4.4; N, 9.8; O, 33.2; S, 10.9.

EXAMPLE 24 The S-1,1-dioxide of7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(pyrid-2'-yl-thiomethyl)-3-cephem-4-carboxylicacid

The title compound of decomposition point 210° was obtained analogouslyto Example 12 by reacting7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-cephalosporanicacid with the 1-oxide of 2-mercapto-pyridine and subsequently oxidizingthe product with 3-chloroperoxybenzoic acid.

C₁₉ H₁₈ N₆ O₇ S₃.2H₂ O (574.6). Calculated: C, 39.7; H, 3.9; N, 14.6.Found: C, 39.9; H, 3.7; N, 14.4.

EXAMPLE 25 The 1,1-dioxide of7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-cephalosporanic acid

160 ml (0.32 mole) of 2 N sodium hydroxide solution is added dropwise toa suspension of 73 g (0.3 mole) of ethyl2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetate (prepared analogously toExample 4, stages 1 to 3) in 300 ccs of ethanol, the mixture is stirredat room temperature for 18 hours, 300 ccs of ether are then addeddropwise and the sodium salt which has crystallized out is filtered offand washed with tetrahydrofuran and ether. The sodium salt is suspendedin 220 ml of methanol, and the equivalent amount of concentratedhydrochloric acid is added. The product is filtered off, washed withether and dried in vacuo, and 52.6 g of2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetic acid are obtained.2-Ethoxyimino-2-(2-aminothiazol-4-yl)-acetic acid is reacted, in theform of the active ester (for example hydroxysuccinimido orpentachlorophenol) with the equivalent amount of the 1,1-dioxide oftert.-butyl 7-aminocephalosporanate (Example 22) in pyridine at roomtemperature to give the 1,1-dioxide of tert.-butyl7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-cephalosporanate ofdecomposition point 180°.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 1.22 (3H, t, --O--CH₂ --CH₃), 1.52 (9H, s,--O--C(CH₃)₃), 2.07 (3H, s, CH₃ --CO--), 4.08 (2H, q, --O--CH₂ --CH₃),4.26 (2H, s, 2--CH₂), 4.78 (2H, q, 3--C--CH₂ --O--), 5.43 (1H, d, 6--H),6.06 (1H, q, 7--H), 6.75 (1H, s, aromatic, H), 7.18 (2H, s, --NH₂) and9.48 (1H, d, --CONH--).

2.4 g (0.0043 mole) of the 1,1-dioxide of tert.-butyl7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-cephalosporanate aredissolved in 12 ccs of trifluoroacetic acid and the solution is stirredat room temperature for 1 hour. After stripping off the trifluoroaceticacid in vacuo, grinding the oil residue with ether and filtering off anddrying the crystals in vacuo, 2.4 g of the title compound in the form ofthe trifluoroacetate of decomposition point 138° are obtained.

C₁₉ H₂₀ F₃ N₅ O₁₁ S₂ (615.5). Calculated: C, 37.1; H, 3.3; N, 11.4; S,10.4. Found: C, 36.8; H, 3.4; N, 11.7; S, 10.4.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 1.22 (3H, t, --O--CH₂ --CH₃), 2.03 (3H, s,CH₃ --CO--), 4.11 (2H, q, --O--CH₂ --CH₃), 4.25 (2H, s, 2--CH₂), 4.83(2H, q, 3--C--CH₂ --O--), 5.43 (1H, d, 6--H), 6.01 (1H, q, 7--H), 6.78(1H, s, aromatic, H) and 9.50 (1H, d, --CONH--). R_(f) value: 0.43 (thinlayer chromatography on silica gel by ethyl acetate/isopropanol/water4:3:2).

EXAMPLE 26 The 1,1-dioxide of 7-[2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetamido]-cephalosporanic acid

The title compound of decomposition point 120° was obtained analogouslyto Example 25.

The title compound contains 13.8% of trifluoroacetic acid; theelementary composition was calculated accordingly.

Calculated: C, 40.1; H, 3.9; N, 11.4; S, 10.4. Found: C, 39.9; H, 3.9;N, 11.2; S, 10.4.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 0.63-1.9 (7H, m, --CH₂ --CH₂ --CH₃), 2.03(3H, s, CH₃ --CO--), 4.08 (2H, t, --O--CH₂ --CH₂ --), 4.25 (2H, d,2--CH₂), 4.85 (2H, q, 3--C--CH₂ --O--), 5.43 (1H, d, 6--H), 6.03 (1H, q,7--H), 6.80 (1H, s, aromatic, H) and 9.55 (1H, d, --CONH).

EXAMPLE 27 The 1,1-dioxide of7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-cephalosporanicacid

The title compound of decomposition point 130° was obtained analogouslyto Example 25. It contains 7.9% of trifluoroacetic acid; the elementarycomposition was calculated accordingly.

Calculated: C, 40.4; H, 3.5; N, 12.6; S, 11.5. Found: C, 39.4; H, 3.6;N, 12.4; S, 11.3.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 2.03 (3H, s, CH₃ --CO--), 4.25 (2H, d,2--CH₂), 4.4-6.4 (5H, m, --OCH₂.CH═CH₂), 4.85 (2H, q, 3--C--CH₂ --O--),5.43 (1H, d, 6--H), 6.01 (1H, q, 7--H), 6.78 (1H, s, aromatic, H) and9.62 (1H, d, --CONH--).

EXAMPLE 28 The 1,1-dioxide of7-[2-(2-aminothiazol-4-yl)-2-(2-bromoallyloxyimino)-acetamido]-cephalosporanicacid

The title compound of decomposition point 115° was obtained anlogouslyto Example 25 from2-(2-bromoallyloxyimino)-2-(2-aminothiazol-4-yl)-acetic acid and the1,1-dioxide of tert.-butyl 7-aminocephalosporanate. It contains 6.2% oftrifluoroacetic acid; the elementary composition was calculatedaccordingly.

Calculated: C, 35.5; H, 2.9; N, 11.1; Br, 12.7; S, 10.2. Found: C, 35.7;H, 3.2; N, 10.8; Br, 12.0; S, 10.2.

NMR (ppm, 60 MHz, (CD₃)₂ SO): 2.03 (3H, s, CH₃ --CO--), 4.25 (2H, d,2--CH₂), 4.67 (2H, s, --O--CH₂ --C--), 4.85 (2H, q, 3--C--CH₂ --O--),5.45 (1H, s, 6--H), 5.85 (2H, q, --C═CH₂), 6.01 (1H, q, 7--H), 6.81 (1H,s, aromatic, H) and 9.75 (1H, d, --NHCO--).

EXAMPLE 29 The 1-R-dioxide of7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-cephalosporanic acid

2.9 g (0.01 mole) of the 1-R-oxide of 7-aminocephalosporanic acid(Example 8) are suspended in 40 ccs of methylene chloride, 2.4 ccs (0.01mole) of bis-trimethylsilyl-acetamide are added and the mixture isstirred at room temperature for 45 minutes. 0.01 mole of an active esterof 2-ethoxyimino-2-(2-aminothiazol-4-yl)-acetic acid is added to theclear solution and the mixture is stirred at room temperature for about20 hours. It is filtered and the residue is triturated with water andethanol. 1.6 g of the title compound of decomposition point 250° areobtained.

C₁₇ H₁₉ N₅ O₈ S₂ (485.5). Calculated: C, 42.1; H, 3.9; N, 14.4; O, 26.4;S, 13.2. Found: C, 42.2; H, 3.8; N, 14.6; O, 26.5; S, 13.4.

NMR (ppm, 60 MHz, (CH₃)₂ SO): 1.22 (3H, t, --O--CH₂ --CH₃), 2.05 (3H, s,CH₃ --CO--), 3.93 (2H, q, 2--CH₂), 4.11 (2H, q, --O--CH₂ --CH₃), 4.80(2H, q, 3--C--CH₂ --O--), 4.90 (1H, d, 6--H), 5.76 (1H, q, 7--H), 6.80(1H, s, aromatic, H), 7.18 (2H, s, --NH₂) and 9.68 (1H, d, --CONH--).

EXAMPLE 30 The monoformate of the S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(.beta.-carboxy-propionylamido)-1,3,4-thiadiazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

792 mg (1.26 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(.beta.-carboxy-propionylamido)-1,3,4-thiadiazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of formic acid (98-100% strength) at roomtemperature. A solution of 278 mg (1.26 mmoles) of 78.3% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran is added dropwise andthe solution is stirred at room temperature for a further 30 minutes.The reaction solution is introduced into 150 ml of diethyl ether, whilestirring, and the precipitate is filtered off and washed with ether.After drying in vacuo, 680 mg of the title compound are obtained.

R_(f) : 0.15 (silica gel, Messrs. Merck; ethyl acetate:methanol:glacialacetic acid=20:10:1)

IR (KBr): 1,774 cm⁻¹ (β-lactam band) NMR (d₆ -DMSO, 60 MHz): δ=3.28 ppm(singlet, 3H, ═N--OCH₃), δ=4.92 ppm (doublet, 1H, 6--CH--), δ=5.82 ppm(quartet, 1H, 7--CH--), δ=6.78 ppm (singlet, 1H, thiazole-H), δ=7.13 ppm(singlet, 2H, --NH₂), δ=8.83 ppm (doublet, 1H, --NH--CO--) and δ=8.13ppm (singlet, 1H, formic acid).

EXAMPLE 31 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(4-pyridyl)-1,3,4-oxadiazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

1.15 g (20 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(4-pyridyl)-1,3,4-oxadiazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of formic acid (98-100% strength) at roomtemperature. A solution of 442 mg (20 mmoles) of 78.3% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran is added dropwise andthe reaction solution is stirred at room temperature for 30 minutes. Thereaction solution is introduced into 250 ml of ether, while stirring,and the precipitate is filtered off, washed with ether and dried invacuo. 1.1 g of the title compound are obtained.

IR (KBr): 1,770 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.83 ppm (singlet, 3H, ═N--OCH₃), δ=4.95 ppm(doublet, 1H, 6--CH--), δ=5.84 ppm (quartet, 1H, 7--CH--), δ=6.80 ppm(singlet, 1H, thiazole-H), δ=7.14 ppm (singlet, 2H, --NH₂), δ=7.89 ppm(multiplet, 2H, pyridyl--H--3.5), δ=8.80 ppm (multiplet, 3H,pyridyl--H--2.6 and --NH--CO--) and δ=8.12 ppm (singlet, 1H, formicacid).

EXAMPLE 32 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(2-pyridyl)-1,3,4-oxadiazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

550 mg (10 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(2-pyridyl)-1,3,4-oxadiazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of formic acid (98-100% strength) at roomtemperature. A solution of 221 mg (10 mmoles) of 78.3% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran is added dropwise andthe reaction solution is stirred at room temperature for 30 minutes. Thereaction solution is introduced into 200 ml of ether, while stirring,and the precipitate is filtered off, washed with ether and dried invacuo. 480 mg of the title compound are obtained.

R_(f) : 0.16 (silica gel, Messrs. Merck; ethyl acetate:methanol:glacialacetic acid=20:10:1).

IR (KBr): 1,776 cm⁻¹ (β-lactam band).

NMR (d₆ -DMSO); 60 MHz): δ=3.83 ppm (singlet, 3H, ═N--OCH₃), δ=4.93 ppm(doublet, 1H, 6--CH--), δ=5.81 ppm (quartet, 1H, 7--CH--), δ=6.77 ppm(singlet, 1H, thiazole-H), δ=7.10 ppm (singlet, 2H, --NH₂), δ=7.56 ppm(multiplet, 1H, pyridyl--H--5), δ=8.00 ppm (multiplet, 2H,pyridyl--H--3,4), δ=8.70 ppm (multiplet, 1H, pyridyl--H--6), δ=8.82 ppm(doublet, 1H, --NH--CO--) and δ=8.06 ppm (singlet, 1H, formic acid).

EXAMPLE 33 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-ethyl-2-trifluoromethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

593 mg (10 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-ethyl-2-trifluoromethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of formic acid (98-100% strength) at roomtemperature. A solution of 232 mg (10 mmoles) of 74% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran is added dropwise andthe solution is stirred at room temperature for a further 30 minutes.The reaction solution is introduced into 150 ml of ether, whilestirring, and the precipitate is filtered off and washed with ether. 520mg of the title compound are obtained.

R_(f) : 0.47 (silica gel, Messrs. Merck; acetone:glacial aceticacid=10:1) and 0.43 (silica gel, Messrs. Merck; ethylacetate:methanol:glacial acetic acid=20:10:1)

IR (KBr): 1,774 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=1.28 ppm (triplet, 3H, N--C--CH₃), δ=3.81 ppm(singlet, 3H, ═N--OCH₃), δ=4.18 ppm (quartet, 2H, --N--CH₂ --C), δ=4.91ppm (doublet, 1H, 6--CH--), δ=5.83 ppm (quartet, 1H, 7--CH--), δ=6.79ppm (singlet, 1H, triazole--H), δ=7.16 ppm (singlet, 2H, --NH₂), δ=8.76ppm (doublet, 1H, --NH--CO--) and δ=8.10 ppm (singlet, 1H, H--AM formicacid).

EXAMPLE 34 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(4,6-diamino-pyrimid-2-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

1.07 g (2 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(4,6-diamino-pyrimid-2-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of formic acid (98-100% strength) at roomtemperature. A solution of 390 mg of 87% pure m-chloroperbenzoic acid in5 ml of tetrahydrofuran is added dropwise and the mixture is stirred atroom temperature for a further 30 minutes. The reaction solution isintroduced into 150 ml of diethyl ether, while stirring, and theprecipitate is filtered off and washed with a large amount of ether.After drying immediately in vacuo, 910 mg of the title compound areobtained.

R_(f) : cannot be determined exactly--substance scarcely migrates inprotic solvents

IR (KBr): 1,770 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.83 ppm (singlet, 1H, ═N--OCH₃), δ=4.89 ppm(doublet, 1H, 6--CH--), δ=5.13 ppm (singlet, 1H, pyrimidyl--H), δ=5.56ppm (quartet, 1H, 7--CH--), δ=6.11 ppm (singlet, 2H, pyrimidyl--NH₂),δ=6.79 ppm (singlet, 3H, thiazole-H and pyrimidyl--NH₂), δ=7.13 ppm(singlet, 2H, thiazole--NH₂), δ=8.65 ppm (doublet, 1H, --NH--CO) andδ=8.11 ppm (singlet, 1H, formic acid).

EXAMPLE 35 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-methyl-2-trifluoromethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

700 mg (1.21 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-methyl-2-trifluoromethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of formic acid (98-100% strength) at roomtemperature. 232 mg of 87% pure m-chloroperbenzoic acid in 5 ml oftetrahydrofuran are added dropwise, while stirring, and the mixture isstirred at room temperature for a further half an hour. It is introducedinto 150 ml of ether, while stirring, and the precipitate is filteredoff and washed with ether. After drying immediately, 540 mg of the titlecompound are obtained.

IR (KBr): 1,781 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.66 ppm (singlet, 3H, --N--CH₃), δ=3.86 ppm(singlet, 3H, ═N--OCH₃), δ=4.94 ppm (doublet, 1H, 6--CH--), δ=5.83 ppm(quartet, 1H, 7--CH--), δ=6.79 ppm (singlet, 1H, thiazole-H), δ=7.13 ppm(singlet, 2H, --NH₂), δ=8.78 ppm (doublet, 1H, --NH--CO--), and δ=8.11ppm (singlet, 1H, formic acid).

EXAMPLE 36 The monoformate of the 1-S-oxide of7β-[2-(2-amino-thiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-ethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

1.5 g (3 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-ethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 25 ml of 98% strength formic acid at roomtemperature. 623 mg (3 mmoles+5% excess) of 87% pure m-chloroperbenzoicacid in 10 ml of tetrahydrofuran are added dropwise and the reactionsolution is stirred at room temperature for 1.2 hours. The reactionmixture is introduced into 300 ml of ether, while stirring, and theprecipitate is filtered off and washed with ether. After drying invacuo, 1.5 g of the title compound are obtained.

IR (KBr): 1,770 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=4.25 ppm (triplet, 3H, --N--O--CH₃), δ=3.74ppm (singlet, ═N--OCH₃), δ=4.00 ppm (multiplet, 2--CH₂ --+N--CH₂ --C),δ=4.94 ppm (doublet, 1H, 6--CH--), δ=5.75 ppm (quartet, 1H, 7--CH--),δ=6.72 ppm (singlet, 1H, thiazole--H), δ=7.14 ppm (singlet, broad,--NH₂), δ=8.55 ppm (singlet, 1H, triazole-H), δ=8.85 ppm (doublet, 1H,--CO--NH--) and δ=8.18 ppm (singlet, 1H, formic acid).

EXAMPLE 37 The monoformate of the 1-S-oxide of7β-[2-(2-amino-thiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(3-thienyl)-1H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

549 mg (0.95 mmole) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(3-thienyl)-1H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of 98% strength formic acid at roomtemperature. 190 mg (0.95 mmole+5% excess) of 87% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran are added dropwise,while stirring, and the reaction solution is stirred at room temperaturefor a further 45 minutes. The reaction mixture is introduced into 250 mlof ether, while stirring, the precipitate is filtered off and theresidue is washed with ether. After drying in vacuo at 37° C., 450 mg ofthe title compound are obtained.

R_(f) : 0.07 (acetone:chloroform:glacial acetic acid=50:50:7), 0.18(methanol:ethyl acetate:glacial acetic acid=10:20:1) and 0.57(acetone:glacial acetic acid=10:1)

IR (KBr): 1,778 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.84 ppm (singlet, 3H, ═N--OCH₃), δ=4.91 ppm(doublet, 1H, 6--CH--), δ=5.79 ppm (quartet, 1H, 7--CH--), δ=6.77 ppm(singlet, 1H, thiazole-H), δ=7.13 ppm (singlet, broad, 2H, --NH₂),δ=7.60 ppm (multiplet, 2H, thienyl-H-4,5), δ=8.05 ppm (singlet, 1H,thienyl-H-2), δ=8.87 ppm (doublet, 1H, --CO--NH--) and δ=8.05 ppm(singlet, 1H, formic acid).

EXAMPLE 38 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(3-furyl)-1H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

266 mg (0.47 mmole) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(3-furyl)-1H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of 98% strength formic acid at roomtemperature. 112 mg (0.47 mmole+5% excess) of 87% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran are added dropwiseand the mixture is stirred at room temperature for a further 30 minutes.The reaction solution is introduced into 100 ml of ether, whilestirring, and the precipitate is filtered off and washed with ether.After drying in vacuo at 37° C., 140 mg of the title compound areobtained.

R_(f) : 0.25 (ethyl acetate:methanol:glacial acetic acid=20:10:1)

IR (KBr): 1,775 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.33 ppm (AB spectrum, 2--CH₂), δ=3.84 ppm(singlet, ═N--OCH₃), δ=4.18 ppm (AB spectrum, 3--CH₂ --S--), δ=4.85 ppm(doublet, 1H, 6--CH--), δ=5.75 ppm (quartet, 1H, 7--CH--), δ=6.77 ppm(multiplet, 2H, thiazole--H+furyl--H--4), δ=7.12 ppm (multiplet, 3H,furyl--H--5+--NH₂), δ=7.70 ppm (singlet, 1H, furyl--H--2), δ=8.78 ppm(doublet, 1H, --CO--NH--) and δ=8.09 ppm (singlet, 1H, formic acid).

EXAMPLE 39 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(2-thienyl)-1H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylic acid

1.16 g (2 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[2-(3-thienyl)-1-H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of 98% strength formic acid at roomtemperature. A solution of 405 mg (2 mmoles+5% excess) of 87% puremetachloroperbenzoic acid in 15 ml of tetrahydrofuran is added dropwise,while stirring, and the mixture is stirred at room temperature for afurther 60 minutes. It is introduced into 200 ml of ether, whilestirring, and the precipitate is filtered off, washed with ether anddried in vacuo at 37° C. over KOH. 1.1 g of the title compound areobtained.

R_(f) : 0.10 (acetone:chloroform:glacial acetic acid=50:50:1), 0.19(ethyl acetate:methanol:glacial acetic acid=20:10:1) and 0.36(acetone:glacial acetic acid=10:1)

IR (KBr): 1,776 cm⁻¹ (β-lactam band).

NMR (d₆ -DMSO, 6. MHz): δ=3.83 ppm (singlet, ═N--OCH₃), δ=4.07 ppm (ABspectrum, 3--CH₂ --S--), δ=4.90 ppm (doublet, 1H, 6--CH--), δ=5.78 ppm(quartet, 1H, 7--CH--), δ=6.77 ppm (singlet, 1H, thiazole-H), δ=7.13 ppm(multiplet, 3H, --NH₂ +thienyl--H--4), δ=7.63 ppm (multiplet, 2H,thienyl-H-3,5), δ=8.76 ppm (doublet, 1H, --CO--NH--) and δ=8.00 ppm(singlet, 1H, formic acid).

EXAMPLE 40 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[1H-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

1.0 g (2 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1H-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of 98% strength formic acid at roomtemperature. 416 mg of m-chloroperbenzoic acid (87% pure) in 5 ml oftetrahydrofuran are added dropwise, while stirring, and the mixture isstirred at room temperature for a further 75 minutes. It is thenintroduced into 200 ml of ether, while stirring, and the precipitate isfiltered off, washed with ether and dried in vacuo at 37° C. over KOH.0.98 g of the title compound is obtained.

R_(f) : 0.11 (ethyl acetate:methanol:glacial acetic acid=20:10:1)

IR (KBr): 1,774 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.86 ppm (singlet, ═N--OCH₃), δ=4.88 ppm(doublet, 1H, 6--CH--), δ=5.80 ppm (quartet, 1H, 7--CH--), δ=6.76 ppm(singlet, 1H, thiazole-H), δ=7.13 ppm (singlet, broad, 2H, --NH₂),δ=8.36 ppm (singlet, 1H, triazole-H), δ=8.72 ppm (doublet, 1H,--CO--NH--) and δ=8.09 ppm (singlet, 1H, formic acid).

EXAMPLE 41 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[1-methyl-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

1.02 g (2 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-methyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of 98% strength formic acid at roomtemperature. A solution of 416 mg (2 mmoles+5% excess) of 87% purem-chloroperbenzoic acid in 10 ml of tetrahydrofuran is added dropwiseand the mixture is stirred at room temperature for a further hour. It isintroduced into 300 ml of ether, while stirring, and the precipitate isfiltered off, washed thoroughly with ether and dried in vacuo. 920 mg ofthe title compound are obtained.

R_(f) : 0.04 (acetone:glacial acetic acid=10:1)

IR (KBr): 1,777 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.53 ppm (singlet, --N--CH₃), δ=3.86 ppm(singlet, --N--OCH₃), δ=4.89 ppm (doublet, 1H, C--H--6), δ=5.79 ppm(quartet, 1H, 7--CH--), δ=6.78 ppm (singlet, 1H, thiazole-H), δ=7.14 ppm(singlet, broad, 2H, --NH₂), δ=8.50 ppm (singlet, 1H, triazole-H),δ=8.76 ppm (doublet, 1H, --NH--CO--) and δ=8.07 ppm (singlet, 1H, formicacid).

EXAMPLE 42 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[1,2-dimethyl-1,3,4-triazol-5-yl-thiomethyl]-ceph-3-em-4-carboxylicacid

523 mg (1 mmole) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1,2-dimethyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of 98% strength formic acid at roomtemperature. A solution of 213 mg (1 mmole+5% excess) of 87% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran is added dropwise,while stirring, and the mixture is stirred at room temperature for afurther hour. It is introduced into 150 ml of ether and the precipitateis filtered off, washed several times with ether and dried in vacuo. 470mg of the title compound are obtained.

R_(f) : 0.06 (acetone:glacial acetic acid=10:1)

IR (KBr): 1,775 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=2.33 ppm (singlet, --CH₃), δ=3.44 ppm(singlet, --N--CH₃), δ=3.86 ppm (singlet, ═N--OCH₃), δ=4.92 ppm(doublet, 1H, 6--CH--), δ=5.82 ppm (quartet, 1H, 7--CH--), δ=6.79 ppm(singlet, 1H, thiazole--H), δ=7.20 ppm (broad absorption, 2H, --NH₂),δ=8.79 ppm (doublet, 1H, --NH--CO--) and δ=8.09 ppm (singlet, 1H, formicacid).

EXAMPLE 43 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(purin-6-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

550 mg (1 mmole) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(purin-6-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of 98% strength formic acid at roomtemperature. A solution of 230 mg (1 mmole+5% excess) of 87% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran is added dropwise andthe mixture is stirred at room temperature for a further 70 minutes. Itis introduced into 200 ml of ether, while stirring, and the precipitateis filtered off, washed several times with ether and dried in vacuo. 530mg of the title compound are obtained.

IR (KBr): 1,770 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.85 ppm (singlet, ═N--OCH₃), δ=4.11 ppm (ABspectrum, 3--CH₂ --S--), δ=4.90 ppm (doublet, 1H, 6--CH--), δ=5.78 ppm(quartet, 1H, 7--CH--), δ=6.77 ppm (singlet, 1H, thiazole-H), δ=7.15 ppm(singlet, broad, 2H, --NH₂), δ=8.43 ppm (singlet, purinyl-8-H), δ=8.66ppm (singlet, 1H, purinyl-2-H), δ=8.77 ppm (doublet, 1H, --NH--CO--) andδ=8.14 ppm (singlet, 1H, formic acid).

EXAMPLE 44 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(2-phenyl-1H-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

1.15 g (2 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(2-phenyl-1H-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 20 ml of 98% strength formic acid at roomtemperature. A solution of 480 mg (2 mmoles+5% excess) of 87% purem-chloroperbenzoic acid in 8 ml of tetrahydrofuran is added dropwise andthe mixture is stirred at room temperature for a further 70 minutes. Itis introduced into 300 ml of ether, while stirring, and the precipitateis filtered off, washed several times with ether and dried. 1.05 g ofthe title compound are obtained.

IR (KBr): 1,776 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.85 ppm (singlet, ═N--OCH₃), δ=4.87 ppm(doublet, 1H, 6--CH--), δ=5.77 ppm (quartet, 1H, 7--CH--), δ=6.74 ppm(singlet, 1H, thiazole--H), δ=7.10 ppm (singlet, broad, 2H, --NH₂),δ=7.42 ppm (multiplet, 2H, phenyl--H--3,4,5), δ=7.91 ppm (multiplet, 2H,phenyl--H--2,6), δ=8.71 ppm (doublet, 1H, --CO--NH--) and δ=8.07 ppm(singlet, 1H, formic acid).

EXAMPLE 45 The hemiformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(pyrimid-4-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

788 mg (1.55 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(pyrimid-4-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of 98% strength formic acid at roomtemperature. A solution of 327 mg (1.55 mmoles+5% excess) of 87% puremeta-chloroperbenzoic acid in 8 ml of tetrahydrofuran is added dropwiseand the mixture is stirred at room temperature for a further hour. It isintroduced into 250 ml of ether and the precipitate is filtered off,washed several times with ether and dried. 720 mg of the title compoundare obtained.

IR (KBr): 1,781 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.84 ppm (singlet, ═N--OCH₃), δ=4.76 ppm (ABspectrum, 3--CH₂ --S--), δ=4.87 ppm (doublet, 6--CH--), δ=5.78 ppm(quartet, 1H, --7--CH--), δ=6.75 ppm (singlet, 1H, thiazole--H), δ=7.12ppm (singlet, broad, 2H, --NH₂), δ=7.41 ppm (quartet, 1H,pyrimidyl--H--5), δ=8.38 ppm (doublet, 1H, pyrimidyl--H--6), δ=8.85 ppm(doublet, 1H, pyrimidyl--H--2), δ=8.73 ppm (doublet, 1H, --CO--NH--) andδ=8.07 ppm (singlet, 1/2H and 1/2 mole of formic acid).

EXAMPLE 46 The hemiformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-phenyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylic acid

748 mg (1.3 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-phenyl-1,3,4-triazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 15 ml of 98% strength formic acid. 273 mg (1.3mmoles+5% excess) of 87% pure m-chloroperbenzoic acid in 8 ml oftetrahydrofuran are added dropwise and the mixture is stirred at roomtemperature for a further hour. The reaction solution is introduced into250 ml of ether, while stirring, and the precipitate is filtered off,washed with ether and dried in vacuo. 600 mg of the title compound areobtained.

IR (KBr): 1,776 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.85 ppm (singlet, ═N--OCH₃), δ=4.83 ppm(doublet, 1H, 6--CH--), δ=5.80 ppm (quartet, 1H, 7--CH--), δ=6.77 ppm(singlet, 1H, thiazole-H), δ=7.13 ppm (singlet, broad, 2H, --NH₂),δ=7.46 ppm (multiplet, 5H, phenyl-H), δ=8.73 ppm (doublet, 1H,--CO--NH--), δ=8.84 ppm (singlet, 1H, triazole-H), and δ=8.06 ppm(singlet, 1/2H and 1/2 mole of formic acid).

EXAMPLE 47 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-phenyl-tetrazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

589 mg (1.03 mmoles) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(1-phenyl-tetrazol-5-yl-thiomethyl)ceph-3-em-4-carboxylic acid are dissolved in 10 ml of 98% strengthformic acid. 214.5 mg (1.03 mmoles+5% excess) of 87% purem-chloroperbenzoic acid in 5 ml of tetrahydrofuran are added dropwise atroom temperature and the mixture is stirred at room temperature for afurther 45 minutes. It is introduced into 250 ml of ether, whilestirring, and the precipitate is filtered off, washed with ether anddried in vacuo. 410 mg of the title compound are isolated.

IR (KBr): 1,776 cm⁻¹ (β-lactam band)

NMR (d₆ -DMSO, 60 MHz): δ=3.86 ppm (singlet, ═N--OCH₃), δ=4.49 ppm (ABspectrum, 3--CH₂ --S--), δ=4.92 ppm (doublet, 6--CH--), δ=5.82 ppm(quartet, 1H, 7--CH--), δ=6.78 ppm (singlet, 1H, thiazole-H), δ=7.15 ppm(broad absorption, 2H, --NH₂), δ=7.66 ppm (multiplet, 5H, phenyl-H),δ=8.79 ppm (doublet, 1H, --CO--NH--) and δ=8.10 ppm (singlet, 1H, formicacid).

EXAMPLE 48 The monoformate of the 1-S-oxide of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(5-carboxymethyl-4-methylthiazol-2-yl-thiomethyl)-ceph-3-em-4-carboxylicacid

500 mg (0.855 mmole) of7β-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-(5-carboxymethyl-4-methyl-thiazol-2-yl-thiomethyl)-ceph-3-em-4-carboxylicacid are dissolved in 10 ml of 98% strength formic acid. 178 mg (0.855mmole+5% excess) of m-chloroperbenzoic acid in 7 ml of tetrahydrofuranare added dropwise and the mixture is stirred at room temperature for afurther 45 minutes. It is then introduced into 200 ml of ether, whilestirring, and the precipitate is filtered off, washed with ether anddried. 340 mg of the title compound are obtained.

IR (KBr): 1,776 cm⁻¹ (β-lactam band).

NMR (d₆ -DMSO, 60 MHz): δ=2.21 ppm (singlet, --CH₃), δ=3.59 ppm (singlet--CH₂ --COOH), δ=3.76 ppm (singlet, ═N--OCH₃), δ=4.89 ppm (doublet,6--CH--), δ=5.81 ppm (quartet, 1H, 7--CH--), δ=6.78 ppm (singlet, 1H,thiazole-H), δ=7.14 ppm (broad absorption, 2H, --NH₂), δ=8.78 ppm(doublet, 1H, --CO--NH--), and δ=8.09 ppm (singlet, 1H, formic acid).

We claim:
 1. A cephem compound of the formula ##STR1286## wherein theOR₂ group is in the syn-position andR₁ is hydrogen or an aminoprotective group known from peptide chemistry; R₂ is hydrogen, alkylhaving 1 to 4 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkinylhaving 3 to 5 carbon atoms, or such alkyl, alkenyl, or alkinylsubstituted byhalogen lower alkoxy carbonyl phenoxy carbonyl carboxylcarbamyl lower alkyl carbamyl hydroxy lower alkyl carbamyl pyrrolidinylcarbonyl morpholinyl carbonyl sulfamyl sulfonyl hydroxy lower alkoxylower alkanoyloxy lower alkyl sulfonyl cycloalkyl having 3 to 6 carbonatoms phenyl nitrophenyl halophenyl lower alkoxyphenyl, or loweralkylphenyl; --COOR₃ is a carboxylic acid group, a physiologicallyacceptable carboxylic acid ester group, or a physiologically acceptablecarboxylate salt group; R₄ is hydrogen or lower alkoxy having 1 to 4carbon atoms; X is SO in the S-configuration or is SO₂ ; and A ishydrogen, halogen, or --CH₂ Y wherein Y is a nucleophilic group which isaliphatic carbonyloxy, hydroxy, alkoxy having 1 to 8 carbon atoms,pyridino, quinolino, isoquinolino, such pyridino, quinolino, orisoquinolino substituted by lower alkyl lower alkoxy, or by carbamyl,carbamyloxy, carbamylthio, such carbamyloxy or carbamylthiomonosubstituted or disubstituted on the nitrogen atom by lower alkyl orby alkylene forming a 5- or 6-membered ring with the nitrogen atom,which ring may be interrupted by a further oxygen, sulfur, or nitrogenatom, or Y is --SR₅ wherein R₅ is aliphatic carbonyl having 1 to 4carbonatoms, benzoyl, toluoyl, a 5-membered heteroaromatic ring wherein 1 ringmember is sulfur or oxygen and 1 to 3 further ring members are nitrogenand the remaining ring members are carbon or wherein 2 to 4 ring membersare nitrogen and the remaining ring members are carbon, such a5-membered heteroaromatic ring fused to a benzene ring, or such a5-membered heteroaromatic ring or 5-membered heteroaromatic ring fusedto a benzene ring wherein said 5-membered heteroaromatic ring issubstituted bylower alkenyl, amino, carboxy, carboxy lower alkylthio,cyano lower alkylthio, lower alkoxy carbonyl lower alkylthio, sulfonyllower alkylthio, pyridyl-N-oxide hydroxy cycloalkyl having 3 to 8 carbonatoms, phenylamino, carboxy lower alkanoylamino, pyridyl, pyridyl loweralkyl, lower alkanoylamino, lower alkanoyl lower alkylamino, carbamyl,carbamyl lower alkyl, morpholinyl carbonyl, phenyl, halophenyl, loweralkoxyphenyl, lower alkylphenyl, hydroxyphenyl, sulfamylphenyl, loweralkyl, or lower alkyl substituted by carboxy, sulfonyl, sulfamyl,phenyl, halophenyl, carbamyl, lower alkyl carbamyl, lower alkoxycarbonyl, halogen, amino, lower alkanoylamino, hydroxy, cyano, loweralkoxy, carboxy lower alkoxy, carbamyl lower alkoxy, lower alkoxycarbamyl lower alkoxy, or phenoxy, or wherein said 5-memberedheteroaromatic ring is substituted by a further 5-membered ringcontaining at least one oxygen, sulfur, or nitrogen atom as a heteroatom or is such a further 5-membered ring substituted bynitro, carbamyl,or carboxy, or wherein R₅ is a 6-membered heteroaromatic ring wherein 1to 4 ring members are nitrogen and the remaining ring members arecarbon, such a 6-membered heteroaromatic ring fused to a benzene ring,such a 6-membered heteroaromatic ring fused to a further 5-membered or6-membered heteroaromatic ring wherein 1 to 3 ring members are nitrogenand the remaining ring members are carbon, or such 6-memberedheteroaromatic ring or 6-membered heteroaromatic ring fused to benzeneor to a further heteroaromatic ring wherein said 6-memberedheteroaromatic ring is substituted bycarboxy lower alkoxy, carboxy loweralkylthio, lower alkoxy carbonyl lower alkylthio, hydroxy, lower alkoxy,lower alkoxy carbonyl lower alkoxy, carboxy, nitro, halogen, loweralkoxy carbonyl, phenyl, lower alkylthio, amino, morpholino, morpholinylcarbonyl, lower alkyl, or lower alkyl substituted bycarboxy, loweralkoxy carboxy, carbamyl, or cyano.
 2. A compound as in claim 1 which isthe 1-S-oxide of7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetimido]-cephalosporanicacid.
 3. A compound as in claim 1 wherein A is --CH₂ Y and Y is anucleophilic group selected from the group consisting of aliphaticcarbonyloxy having 1 to 4 carbon atoms, hydroxy, and alkoxy having 1 to8 carbon atoms.
 4. A compound as in claim 1 wherein R₄ is hydrogen.
 5. Acompound as in claim 3 wherein R₄ is hydrogen.
 6. A cephem compound asin claim 1 wherein X is SO in the S-configuration.
 7. A cephem compoundas in claim 1 wherein X is SO₂.
 8. A pharmaceutical composition for thetreatment of bacterial infections comprising an effective amount of acephem compound as in claim 1 together with a pharmaceuticallyacceptable carrier.
 9. The method of treating a bacterial infection in apatient suffering therefrom which comprises orally or parenterallyadministering to said patient an effective amount of a cephem compoundas in claim 1.